FABHALTA 200mg capsules medication leaflet

FABHALTA 200 mg hard capsules

Each capsule contains iptacopan hydrochloride monohydrate equivalent to 200 mg iptacopan.

For the full list of excipients, see section 6.1.

Hard capsule (capsule)

Size 0 pale yellow, opaque hard capsule (21.2 to 22.2 mm) with “LNP200” on the body and “NVR”on the cap, containing white or almost white to pale purplish-pink powder.

Paroxysmal nocturnal haemoglobinuria

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

Complement 3 glomerulopathy

FABHALTA is indicated for the treatment of adult patients with complement 3 glomerulopathy (C3G)in combination with a renin-angiotensin system (RAS) inhibitor, or in patients who are RAS-inhibitorintolerant, or for whom a RAS inhibitor is contraindicated (see section 5.1).

The recommended dose is 200 mg taken orally twice daily.

Healthcare professionals should advise patients about the importance of adherence to the dosingschedule. In patients with PNH, adherence is important to minimise the risk of haemolysis (seesection 4.4).

If a dose or doses are missed, the patient should be advised to take one dose as soon as possible (evenif it is shortly before the next scheduled dose) and then to resume the regular dosing schedule. Patientswith PNH who have missed several consecutive doses should be monitored for potential signs andsymptoms of haemolysis.

PNH is a disease that requires chronic treatment. Discontinuation of this medicinal product is notrecommended unless clinically indicated (see section 4.4).

Patients with PNH switching from anti-C5 (eculizumab, ravulizumab) or other PNH therapies toiptacopan

To reduce the potential risk of haemolysis with abrupt treatment discontinuation:

* For patients switching from eculizumab, iptacopan should be initiated no later than 1 week afterthe last dose of eculizumab.

* For patients switching from ravulizumab, iptacopan should be initiated no later than 6 weeksafter the last dose of ravulizumab.

Switches from complement inhibitors other than eculizumab and ravulizumab have not been studied.

Patients with C3G after kidney transplantation (recurrent C3G)

Diagnosis of recurrent C3G should be made based on histological C3 deposition in the glomeruli ofthe transplanted kidney. C3 deposition may be detected in a routine post-transplantation biopsy;otherwise, a biopsy should be performed when clinical signs indicate recurrent C3G. As done in study

X2202 (see section 5.1), treatment with iptacopan can be started before the onset of clinical signs suchas estimated glomerular filtration rate (eGFR) decrease or urine protein-to-creatinine ratio (UPCR)increase. There is limited experience with the use of iptacopan in patients with recurrent C3G aftertransplantation in clinical studies (see section 5.1).

No dose adjustment is required for patients 65 years of age and older (see section 5.2).

No dose adjustment is required in patients with mild (eGFR between 60 and <90 ml/min) or moderate(eGFR between 30 and <60 ml/min) renal impairment. No data are currently available in patients withsevere renal impairment or on dialysis and no dose recommendations can be given (see section 5.2).

The use of iptacopan is not recommended in patients with severe hepatic impairment (Child-Pughclass C). No dose adjustment is required for patients with mild (Child-Pugh class A) or moderate(Child-Pugh class B) hepatic impairment (see section 5.2).

The safety and efficacy of iptacopan in children aged below 18 years have not been established. Nodata are available.

For oral use.

This medicinal product may be taken with or without food (see section 5.2).

* Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

* Patients who are not currently vaccinated against Neisseria meningitidis and Streptococcuspneumoniae, unless the risk of delaying treatment outweighs the risk of developing an infectionfrom these encapsulated bacteria (see section 4.4).

* Patients with unresolved infection caused by encapsulated bacteria, including Neisseriameningitidis, Streptococcus pneumoniae or Haemophilus influenzae type B, at treatmentinitiation.

Serious infections caused by encapsulated bacteria

The use of complement inhibitors, such as iptacopan, may predispose individuals to serious, life-threatening or fatal infections caused by encapsulated bacteria. To reduce the risk of infection, allpatients must be vaccinated against encapsulated bacteria, including Neisseria meningitidis and

Streptococcus pneumoniae. It is recommended to vaccinate patients against Haemophilus influenzaetype B if vaccine is available. Healthcare professionals should refer to local vaccination guidelinerecommendations.

Vaccines should be administered at least 2 weeks prior to administration of the first dose of iptacopan.

If treatment must be initiated prior to vaccination, patients should be vaccinated as soon as possibleand provided with antibacterial prophylaxis until 2 weeks after vaccine administration.

If necessary, patients may be revaccinated in accordance with local vaccination guidelinerecommendations.

Vaccination reduces, but does not eliminate, the risk of serious infection. Serious infection mayrapidly become life-threatening or fatal if not recognised and treated early. Patients should beinformed of and monitored for early signs and symptoms of serious infection. Patients should beimmediately evaluated and treated if infection is suspected. The use of iptacopan during treatment ofserious infection may be considered following an assessment of the risks and benefits (seesection 4.8).

PNH laboratory monitoring

Patients with PNH receiving iptacopan should be monitored regularly for signs and symptoms ofhaemolysis, including measuring lactate dehydrogenase (LDH) levels.

Monitoring of PNH manifestations after treatment discontinuation

If treatment must be discontinued, patients with PNH should be closely monitored for signs andsymptoms of haemolysis for at least 2 weeks after the last dose. These signs and symptoms include,but are not limited to, elevated LDH levels along with sudden decrease in haemoglobin or PNH clonesize, fatigue, haemoglobinuria, abdominal pain, dyspnoea, dysphagia, erectile dysfunction, or majoradverse vascular events (MAVEs), including venous or arterial thrombosis. If treatmentdiscontinuation is necessary, alternative therapy should be considered.

If haemolysis occurs after discontinuation of iptacopan, restarting treatment should be considered.

Co-administration with other medicinal products

Concomitant use of iptacopan with strong inducers of CYP2C8, UGT1A1, PgP, BCRP and

OATP1B1/3 has not been studied clinically; therefore, concomitant use is not recommended due to thepotential for reduced efficacy of iptacopan (see section 4.5). If an alternative concomitant medicinalproduct cannot be identified, patients with PNH should be monitored for potential signs and symptomsof haemolysis.

Treatment of patients with C3G

Patients with C3G treated with immunosuppressant medicinal products may show modest proteinuriareduction with iptacopan, which is likely linked to a more treatment-resistant nature of C3G in thesepatients.

There is no experience with the use of iptacopan in patients with C3G in native kidney who haveproteinuria below 1 g/g at treatment initiation.

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

FABHALTA therapy with the patient and provide them with the patient information pack. The patientshould be instructed to seek prompt medical care if they experience any sign or symptom of seriousinfection or serious haemolysis (patients with PNH) following treatment discontinuation.

Effects of other medicinal products on iptacopan

Strong inducers of CYP2C8, UGT1A1, PgP, BCRP and OATP1B1/3

Although concomitant administration of iptacopan with strong inducers of CYP2C8, UGT1A1, PgP,

BCRP and OATP1B1/3, such as rifampicin, has not been studied clinically, concomitant use withiptacopan is not recommended due to the potential for reduced efficacy of iptacopan (see section 4.4).

Effects of iptacopan on other medicinal products

In vitro data showed iptacopan has potential for induction of CYP3A4 and may decrease the exposureof sensitive CYP3A4 substrates. The concomitant use of iptacopan and sensitive CYP3A4 substrateshas not been studied clinically. Caution should be exercised if co-administration of iptacopan withsensitive CYP3A4 substrates is required, especially for those with a narrow therapeutic index (e.g.carbamazepine, ciclosporin, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus).

CYP2C8 substrates

In vitro data showed iptacopan has potential for time-dependent inhibition of CYP2C8 and mayincrease the exposure of sensitive CYP2C8 substrates, such as repaglinide, dasabuvir or paclitaxel.

The concomitant use of iptacopan and sensitive CYP2C8 substrates has not been studied clinically.

Caution should be exercised if co-administration of iptacopan with sensitive CYP2C8 substrates isrequired.

There are no or limited amount of data from the use of iptacopan in pregnant women. Animal studiesdo not indicate direct or indirect harmful effects with respect to reproductive toxicity at exposuresbetween 2- and 8-fold the human exposure at the maximum recommended human dose (MRHD) (seesection 5.3).

PNH in pregnancy is associated with adverse maternal outcomes, including worsening cytopenias,thrombotic events, infections, bleeding, miscarriages and increased maternal mortality, as well asadverse foetal outcomes, including foetal death and premature delivery.

C3G in pregnancy may be associated with adverse maternal outcomes, in particular pre-eclampsia andmiscarriage, as well as adverse foetal outcomes including prematurity and low birth weight.

The use of iptacopan in pregnant women or women planning to become pregnant may only beconsidered following a careful assessment of the risk and benefits, if necessary.

It is unknown whether iptacopan is excreted in human milk. There are no data on the effects ofiptacopan on the breast-fed newborn/infant or on milk production.

A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinuebreast-feeding or to discontinue/abstain from FABHALTA therapy taking into account the benefit ofbreast feeding for the child and the benefit of therapy for the woman.

There are no data on the effect of iptacopan on human fertility. Available non-clinical data do notsuggest an effect of iptacopan treatment on fertility (see section 5.3).

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

The most commonly reported adverse reactions in adult patients with PNH were upper respiratorytract infection (18.9%), headache (18.3%) and diarrhoea (11.0%). The most commonly reportedserious adverse reaction was urinary tract infection (1.2%).

The most commonly reported adverse reaction in adult patients with C3G was upper respiratory tractinfection (12.9%). The most commonly reported serious adverse reaction was pneumococcal infection(1%).

Table 1 shows the adverse reactions observed in the clinical studies with iptacopan in patients with

PNH and C3G. 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), rare (≥1/10 000 to <1/1 000) or very rare (<1/10 000).

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

Table 1 Adverse reactions

System Organ Class Frequency category

Adverse reaction PNH C3G

Upper respiratory tract infection1 Very common Very common

Urinary tract infection2 Common

Bronchitis3 Common

Pneumococcal infection4 Common

Pneumonia bacterial Uncommon

Platelet count decreased Common

Headache5 Very common

Dizziness Common

Diarrhoea Very common

Abdominal pain6 Common

Nausea Common

Urticaria Uncommon

Arthralgia Common1 Upper respiratory tract infection includes preferred terms influenza, nasopharyngitis, pharyngitis, rhinitis,sinusitis, upper respiratory tract infection, and viral upper respiratory tract infection.2 Urinary tract infection includes preferred terms urinary tract infection and cystitis escherichia.3 Bronchitis includes preferred terms bronchitis, bronchitis haemophilus and bronchitis bacterial.4 Pneumococcal infection includes preferred terms pneumonia pneumococcal and pneumococcal sepsis.5 Headache includes preferred terms headache and head discomfort.6 Abdominal pain includes preferred terms abdominal pain, abdominal pain upper, abdominal tenderness andabdominal discomfort.

In PNH clinical studies 1/164 (0.6%) patients with PNH reported serious bacterial pneumonia whilereceiving treatment with iptacopan; the patient had been vaccinated against Neisseria meningitidis,

Streptococcus pneumoniae and Haemophilus influenzae type B and recovered following treatmentwith antibiotics while continuing treatment with iptacopan.

In C3G completed clinical studies, 1 patient with C3G reported serious pneumococcal infection withpneumonia and sepsis while receiving treatment with iptacopan; the patient had been vaccinatedagainst Neisseria meningitidis, Streptococcus pneumoniae and Haemophilus influenzae type B andrecovered following treatment with antibiotics. Iptacopan treatment was interrupted and restarted afterrecovery.

Platelet count decreased in patients with PNH

Decrease in platelet count events was reported in 12/164 (7%) patients with PNH. Of these, 5 patientshad events of mild severity, 5 had moderate events and 2 had severe events. Patients with severeevents had concurrent anti-platelet antibodies or idiopathic bone marrow aplasia with pre-existingthrombocytopenia. The events started within the first 2 months of iptacopan treatment in 7/12 patients,and after a longer exposure (111 to 951 days) in 5/12 patients. At the cut-off date, 7 (58%) patientshad recovered or events were resolving and iptacopan treatment was continued throughout in allpatients.

Blood cholesterol and blood pressure increases in patients with PNH

In patients treated with iptacopan 200 mg twice a day in PNH clinical studies, mean increases frombaseline of approximately 0.7 mmol/l were seen at month 6 for total cholesterol and LDL-cholesterol.

The mean values remained within the normal ranges. Increases in blood pressure, particularly diastolicblood pressure (DBP), were observed (mean increase 4.7 mmHg at month 6). The mean DBP did notexceed 80 mmHg. Total cholesterol, LDL-C and DBP increases correlated with increases inhaemoglobin (improvement in anaemia) in patients with PNH (see section 5.1).

In patients treated with iptacopan 200 mg twice a day in the C3G clinical study, no clinically relevantdifferences were observed in total cholesterol, LDL-cholesterol or blood pressure compared toplacebo.

Heart rate decrease in patients with PNH

In patients treated with iptacopan 200 mg twice a day in PNH clinical studies, a mean decrease inheart rate of approximately 5 bpm was seen at month 6 (mean of 68 bpm).

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.

During clinical studies, a few patients took up to 800 mg iptacopan daily and this was well tolerated.

In healthy volunteers, the highest dose was 1 200 mg administered as a single dose and this was welltolerated.

General supportive measures and symptomatic treatment should be initiated in cases of suspectedoverdose.

Pharmacotherapeutic group: Immunosuppressants, complement inhibitors, ATC code: L04AJ08

Iptacopan is a proximal complement inhibitor that targets Factor B (FB) to selectively inhibit thealternative pathway. In PNH, inhibition of FB in the alternative pathway of the complement cascadeprevents the activation of C3 convertase and the subsequent formation of C5 convertase to controlboth C3-mediated extravascular haemolysis (EVH) and terminal complement-mediated intravascularhaemolysis (IVH).

In C3G, overactivation of the complement alternative pathway leads to deposition of C3 within theglomeruli, triggering inflammation, glomerular injury, and kidney fibrosis. Iptacopan selectivelyblocks the alternative pathway overactivation by inhibiting the alternative pathway related C3convertase activity, leading to decreased cleavage of C3 and reduced C3 deposition in the kidney.

The onset of inhibition of the alternative complement pathway, measured using an ex vivo alternativepathway assay, Bb levels (fragment b of Factor B) and plasma levels of C5b-9, was ≤2 hours after asingle iptacopan dose in healthy volunteers.

A comparable effect of iptacopan was observed in patients with PNH previously exposed to anti-C5agents and treatment-naïve patients.

In treatment-naïve PNH patients, iptacopan 200 mg twice daily reduced LDH by >60% compared tobaseline after 12 weeks and maintained the effect through to the end of the study.

In patients with C3G, the mean serum C3 level increased by 249% compared to baseline at day 14 ofiptacopan treatment, reflecting inhibition of pathological C3 cleavage. The plasma soluble C5b-9 andurine soluble C5b-9 decreased from baseline by 71.8% and 92.1%, respectively, on the firstobservation at day 30 of treatment with iptacopan 200 mg twice daily. The effect was sustained overthe observation period of 12 months. A reduction of glomerular C3 deposition at 6 months was alsoobserved based on C3 deposit score change.

In a QTc clinical study in healthy volunteers, single supra-therapeutic iptacopan doses up to 1 200 mg(which provided greater than 4-fold exposure of the 200 mg twice daily dose), showed no effect oncardiac repolarisation or QT interval.

Paroxysmal nocturnal haemoglobinuria

The efficacy and safety of iptacopan in adult patients with PNH were evaluated in two multicentre,open-label, 24-week phase III studies: an active comparator-controlled study (APPLY-PNH) and asingle-arm study (APPOINT-PNH).

APPLY-PNH: anti-C5 treatment experienced patients with PNH

APPLY-PNH enrolled adult PNH patients (RBC clone size ≥10%) with residual anaemia(haemoglobin <10 g/dl) despite previous treatment with a stable regimen of anti-C5 treatment (eithereculizumab or ravulizumab) for at least 6 months prior to randomisation.

Patients (N=97) were randomised in 8:5 ratio either to receive iptacopan 200 mg orally twice daily(N=62) or to continue anti-C5 treatment (eculizumab N=23; or ravulizumab N=12) throughout theduration of the 24-week randomised controlled period (RCP). Randomisation was stratified based onprior anti-C5 treatment and transfusion history within the last 6 months.

Demographics and baseline disease characteristics were generally well balanced between treatmentgroups. At baseline, patients had a mean (standard deviation [SD]) age of 51.7 (16.9) years (range 22-84) and 49.8 (16.7) years (range 20-82) in the iptacopan and anti-C5 groups, respectively and 69% ofpatients were female in both groups. The mean (SD) haemoglobin was 8.9 (0.7) g/dl and 8.9 (0.9) g/dl,in the iptacopan and anti-C5 group, respectively. Fifty-seven percent (iptacopan group) and 60% (anti-

C5 group) of patients received at least one transfusion in the 6 months prior to randomisation.

Amongst those, the mean (SD) number of transfusions was 3.1 (2.6) and 4.0 (4.3) in the iptacopan andanti-C5 group, respectively. The mean (SD) LDH level was 269.1 (70.1) U/l in the iptacopan groupand 272.7 (84.8) U/l in the anti-C5 group. The mean (SD) absolute reticulocyte count was193.2 (83.6) 109/l in the iptacopan group and 190.6 (80.9) 109/l in the anti-C5 group. The mean (SD)total PNH RBC clone size (Type II + III) was 64.6% (27.5%) in the iptacopan group and 57.4%(29.7%) in the anti-C5 group.

During the RCP, 1 patient in the iptacopan group discontinued treatment due to pregnancy; no patientsin the anti-C5 group discontinued.

Efficacy was based on two primary endpoints to demonstrate superiority of iptacopan to anti-C5 inachieving haematological response after 24 weeks of treatment, without a need for transfusion, byassessing the proportion of patients demonstrating: 1) sustained increase of ≥2 g/dl in haemoglobinlevels from baseline (haemoglobin improvement) and/or 2) sustained haemoglobin levels ≥12 g/dl.

Iptacopan demonstrated superiority to anti-C5 therapy for the two primary endpoints, as well as forseveral secondary endpoints including transfusion avoidance, changes from baseline in haemoglobinlevels, Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scores, absolutereticulocyte counts (ARCs) and annualised rate of clinical breakthrough haemolysis (see Table 2).

The treatment effect of iptacopan on haemoglobin was seen as early as day 7 and sustained during thestudy (see Figure 1).

Table 2 Efficacy results for the 24-week randomised treatment period in APPLY-PNH

Endpoints Iptacopan Anti-C5 Difference(N=62) (N=35) (95% CI)p-value

Primary endpoints

Number of patients achieving 51/60b 0/35bhaemoglobin improvement (sustainedincrease of haemoglobin levels ≥2 g/dlfrom baselinea in the absence oftransfusions)

Response ratec (%) 82.3 2.0 80.2(71.2, 87.6)<0.0001

Number of patients achieving sustained 42/60b 0/35bhaemoglobin level ≥12 g/dla in the absenceof transfusions

Response ratec (%) 68.8 1.8 67.0(56.4, 76.9)<0.0001

Secondary endpoints

Number of patients avoiding transfusiond,e 59/62b 14/35b

Transfusion avoidance ratec (%) 94.8 25.9 68.9(51.4, 83.9)<0.0001

Haemoglobin level change from baseline 3.60 -0.06 3.66(g/dl) (adjusted meanf) (3.20, 4.12)<0.0001

FACIT-Fatigue score change from 8.59 0.31 8.29baseline (adjusted meang) (5.28, 11.29)<0.0001

Clinical breakthrough haemolysish,i, % 3.2 (2/62) 17.1 (6/35)(n/N)

Annualised rate of clinical breakthrough 0.07 0.67 RR=0.10haemolysis (0.02, 0.61)0.01

Absolute reticulocyte count change from -115.8 0.3 -116.2baseline (109/l) (adjusted meang) (-132.0, -100.3)<0.0001

LDH ratio to baseline (adjusted geometric 0.96 0.98 Ratio = 0.99meang) (0.89, 1.10)0.84

MAVEsh % 1.6 0(n/N) (1/62)

Annualised rate of MAVEsh 0.03 0 0.03(-0.03, 0.10)0.32

RR: rate ratio; LDH: lactate dehydrogenase; MAVEs: major adverse vascular eventsa,d,h Assessed between days 126 and 168(a), 14 and 168(d), 1 and 168(h).b Based on observed data among evaluable patients. (In 2 patients with partially missing central haemoglobindata between days 126 and 168, the haematological response could not be established unequivocally. Thehaematological response was derived using multiple imputation. These patients did not discontinue.)c Response rate reflects the model estimated proportion.e Transfusion avoidance is defined as absence of administration of packed red blood cell transfusions betweendays 14 and 168 or meeting the criteria for transfusion between days 14 and 168.f,g Adjusted mean assessed between days 126 and 168, values within 30 days after transfusion wereexcluded(f)/included(g) in the analysis.i Clinical breakthrough haemolysis is defined as meeting clinical criteria (either decrease of haemoglobin level≥2 g/dl compared to the last assessment or within 15 days, or signs or symptoms of gross haemoglobinuria,painful crisis, dysphagia or any other significant clinical PNH-related signs and symptoms) and laboratorycriteria (LDH >1.5 x ULN and increased as compared to the last 2 assessments).

Figure 1 Mean haemoglobin level* (g/dl) during 24-week randomised treatment period in

APPLY-PNH12 g/dl

Baseline Day 7 Day 14 Day 28 Day 42 Day 56 Day 84 Day 112 Day 126 Day 140 Day 154 Day 168

Visit

Anti-C5 Iptacopan

*Note: The figure includes all haemoglobin data collected in the study, including those values within 30 daysafter RBC transfusion.

Treatment extension

A total of 95 APPLY-PNH patients entered the 24-week treatment extension period, where all patientsreceived iptacopan, resulting in a total exposure of up to 48 weeks. The efficacy results at week 48were consistent with those at week 24 and demonstrated sustained efficacy of iptacopan treatment.

APPOINT-PNH: Complement inhibitor-naïve study

APPOINT-PNH was a single-arm study in 40 adult PNH patients (RBC clone size ≥10%) withhaemoglobin <10 g/dl and LDH >1.5 x ULN who were not previously treated with a complementinhibitor. All 40 patients received iptacopan 200 mg orally twice daily during the 24-week open-labelcore treatment period.

At baseline, patients had a mean (SD) age of 42.1 (15.9) years (range 18-81) and 43% were female.

The mean (SD) haemoglobin was 8.2 (1.1) g/dl. Seventy percent of patients received at least onetransfusion in the 6 months prior to treatment. Amongst those the mean (SD) number of transfusionswas 3.1 (2.1). The mean (SD) LDH level was 1 698.8 (683.3) U/l, and the mean (SD) absolutereticulocyte count was 154.3 (63.7) 109/l. The mean (SD) total PNH RBC clone size (Type II + III)was 42.7% (21.2%). No patients discontinued from the core treatment period of the study.

Efficacy was based on the primary endpoint assessing the effect of iptacopan treatment on theproportion of patients achieving haemoglobin improvement (sustained increase of ≥2 g/dl inhaemoglobin levels from baseline, without a need for RBC transfusion, after 24 weeks).

See Table 3 for detailed efficacy results and see Figure 2 for the mean LDH level change during the24-week core treatment period.

Mean haemoglobin level (SD) g/dl

Table 3 Efficacy results for the 24-week core treatment period in APPOINT-PNH

Endpoints Iptacopan(N=40)95% CI

Primary endpoint

Number of patients achieving haemoglobin improvement (sustained 31/33bincrease of haemoglobin levels ≥2 g/dl from baselinea in the absence oftransfusions)

Response ratec (%) 92.2(82.5, 100.0)d

Secondary endpoints

Number of patients achieving sustained haemoglobin level ≥12 g/dla in the 19/33babsence of transfusions

Response ratec (%) 62.8(47.5, 77.5)

Number of patients avoiding transfusione,f 40/40b

Transfusion avoidance ratec (%) 97.6(92.5, 100.0)

Haemoglobin level change from baseline (g/dl) +4.3(adjusted meang) (3.9, 4.7)

Clinical breakthrough haemolysisi,j, % (n/N) 0/40

Annualised rate of clinical breakthrough haemolysis 0.0(0.0, 0.2)

Absolute reticulocyte count change from baseline (109/l) -82.5(adjusted meanh) (-89.3, -75.6)

LDH percent change from baseline -83.6(adjusted meanh) (-84.9, -82.1)

Percentage of patients with MAVEsj 0.0a,e,j Assessed between days 126 and 168(a), 14 and 168(e), 1 and 168(j).b Based on observed data among evaluable patients. (In 7 patients with partially missing central haemoglobindata between days 126 and 168, the haematological response could not be established unequivocally. Thehaematological response was derived using multiple imputation. These patients did not discontinue.)c Response rate reflects the model estimated proportion.d The threshold for demonstration of benefit was 15%, representing the rate that would have been expected onanti-C5 treatment.f Transfusion avoidance is defined as absence of administration of packed red blood cell transfusions betweendays 14 and 168 or meeting the criteria for transfusion between days 14 and 168.g,h Adjusted mean assessed between days 126 and 168, values within 30 days after transfusion wereexcluded(g)/included(h) in the analysis.i Clinical breakthrough haemolysis defined as meeting clinical criteria (either decrease of haemoglobin level≥2 g/dl compared to the latest assessment or within 15 days; or signs or symptoms of grosshaemoglobinuria, painful crisis, dysphagia or any other significant clinical PNH-related signs andsymptoms) and laboratory criteria (LDH >1.5 x ULN and increased as compared to the last 2 assessments).

Figure 2 Mean LDH level (U/l) during 24-week core treatment period in APPOINT-PNH375 U/l (1.5 x ULN)

Visits

Treatment: Iptacopan

Treatment extension

All 40 APPOINT-PNH patients entered the 24-week treatment extension period, where all patientscontinued iptacopan treatment, resulting in a total exposure of up to 48 weeks. The efficacy results atweek 48 were consistent with those at week 24 demonstrating sustained efficacy of iptacopantreatment.

Complement 3 glomerulopathy

The efficacy and safety of iptacopan for the treatment of C3G were evaluated in a total of 101 patientswith C3G in one pivotal phase III study (APPEAR-C3G, in patients with native kidney, N=74) andtwo supportive open-label studies (study X2202 in patients with native kidney (N=16) and patientswith recurrent C3G (N=11), and a roll-over extension study).

APPEAR-C3G

APPEAR-C3G, a multicentre, randomised, double-blind, placebo-controlled study, enrolled 74 adultpatients with biopsy-confirmed C3G, UPCR ≥1 g/g, and eGFR ≥30 ml/min/1.73 m2.

Patients were randomised (1:1) to receive either iptacopan 200 mg orally twice daily (N=38) orplacebo (N=36) for 6 months, followed by a 6-month open-label treatment period in which patientsreceived iptacopan 200 mg orally twice daily. All 74 patients completed the double-blind period and73 patients completed the open-label treatment period with iptacopan.

Patients were on a stable maximally tolerated dose of a renin-angiotensin system (RAS) inhibitor.

Randomisation was stratified according to whether or not patients were receiving concomitantimmunosuppressive therapy (i.e. corticosteroid and/or mycophenolate mofetil/sodium [MMF/MPS]).

All of these therapies (i.e. RAS inhibitors, corticosteroids and MMF/MPS) were required to be atstable doses 90 days prior to randomisation and throughout the study.

At baseline, patients had a mean (standard deviation [SD]) age of 26.1 (10.4) years (range 18-52) and29.8 (10.8) years (range 18-60) in the iptacopan and placebo groups, respectively. At the time of C3Gdiagnosis, 40% (iptacopan) and 17% (placebo) of patients were <18 years old. Females were 29%(iptacopan) and 44% (placebo). The geometric mean UPCR was 3.33 g/g and 2.58 g/g in the iptacopanand placebo groups, respectively. The mean modelled historical eGFR slope prior to randomisationwas -10.75 vs. -7.64 ml/min/1.73 m2 per year in iptacopan and placebo arms, respectively. The mean(SD) eGFR was 89.3 (35.2) ml/min/1.73 m2 and 99.2 (26.9) ml/min/1.73 m2 in the iptacopan andplacebo groups, respectively. Subtypes were C3 glomerulonephritis (C3GN) in 68% (iptacopan) and89% (placebo) of patients, and dense deposit disease (DDD) in 23.7% (iptacopan) and 2.8% (placebo).

A stable dose of immunosuppressive therapy with corticosteroid and/or MMF/MPS was used by 42%(iptacopan) and 47% (placebo) of patients.

The primary efficacy endpoint was percent reduction in 24-hour UPCR compared to baseline after6 months of treatment.

Mean LDH level (SD) U/l

Iptacopan was superior to placebo, with a statistically significant 35.1% reduction (95% CI: 13.8%,51.1%, 1-sided p=0.0014) in 24-hour UPCR from baseline compared to placebo after 6 months oftreatment (-30.2% and +7.6% for iptacopan and placebo, respectively). The effect of iptacopan on 24-hour UPCR was sustained up to 12 months (-40.0% from baseline). Patients who switched fromplacebo to iptacopan in the 6-month open-label treatment period experienced a 31.0% reduction in 24-hour UPCR from month 6 to month 12. First morning void (FMV) UPCR trajectory is described in

Figure 3.

In a post-hoc analysis, iptacopan reduced the percentage of patients with nephrotic range proteinuria(defined as UPCR ≥3 g/g) from 55.3% at baseline to 31.6% and 36.8% at months 6 and 12,respectively. The percentage of patients with nephrotic range proteinuria randomised to placeboincreased from 30.6% at baseline to 41.7% at month 6. After switching to iptacopan treatment, itdecreased to 27.8% at month 12.

Figure 3 Geometric mean percent change from baseline in FMV UPCR up to 12 months(APPEAR-C3G)

Double-blind period Open-label period

Placebo Iptacopan switch

Iptacopan

BL

Visit (day)

Iptacopan

Placebo - Iptacopan

Iptacopan treatment for 6 months resulted in a numerical improvement of 2.2 ml/min/1.73 m2 (95%

CI: -2.7, 7.1, 1-sided p=0.3241) in eGFR from baseline compared to placebo (1.3 and

- 0.9 ml/min/1.73 m2 for iptacopan and placebo, respectively). The eGFR remained stable during the12 months duration of the study in the iptacopan treatment arm (+0.4 ml/min/1.73 m2 from baseline).

Iptacopan treatment for 6 months resulted in a mean difference in glomerular C3 deposition of -1.9(95% CI: -3.3, -0.5; nominal 1-sided p=0.0053) from baseline compared to placebo. Change frombaseline on iptacopan was -0.78 (95% CI: -1.81, 0.25) compared to an increase of 1.09 (95% CI: 0.11,2.08) with placebo.

X2202 and roll-over extension study

The efficacy of iptacopan in adults with C3G was supported by an open-label phase II study X2202 inpatients with C3G in native kidney (N=16) and patients with recurrent C3G post-kidneytransplantation (N=11) for 3 months.

Diagnosis of recurrent C3G required histological assessment of glomerular C3 staining intensity on arecent biopsy of the transplanted kidney. The baseline mean age was 35 years (range 18-70), thegeometric mean UPCR was 0.32 g/g, the mean (SD) eGFR was 52.2 (17.29) ml/min/1.73 m2, and themedian C3 deposit score was 3 on a scale of 0-12 at baseline. All patients were on MMF/MPS and/orcorticosteroids in addition to calcineurin inhibitors.

In patients with native kidney, iptacopan resulted in a statistically significant 45% (-162.6 g/mol)reduction in 24-hour UPCR (p=0.0003) at 3 months. In patients with recurrent C3G, iptacopansignificantly reduced the histological C3 deposit score by 2.50 (p=0.0313) at 3 months.

Percentage change (95% CI)

Most (n=26) patients from the study transitioned to a roll-over extension study to receive iptacopan200 mg twice daily for up to 39 months. Mean UPCR and eGFR remained stable throughout the studyin the 16 patients with C3G in native kidney. Among the 10 subjects with recurrent C3G aftertransplantation, 2 patients dropped out due to deterioration of renal function. In the other8 participants, eGFR and UPCR remained essentially constant until the end of the observation period(up to 48 months).

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

FABHALTA in one or more subsets of the paediatric population in PNH and C3G (see section 4.2 forinformation on paediatric use).

Following oral administration, iptacopan reached peak plasma concentrations approximately 2 hourspost dose. At the recommended dosing regimen of 200 mg twice daily, steady state is achieved inapproximately 5 days with minor accumulation (1.4-fold). In healthy volunteers, steady-state Cmax,ss(geo-mean (%CV)) was 4 020 ng/ml (23.8%) and AUCtau,ss was 25 400 ng*hr/ml (15.2%). Inter- andintra-subject variability in iptacopan pharmacokinetics is low to moderate.

Results from a food-effect study with a high-fat high-calorie meal in healthy volunteers indicated that

Cmax and area under the curve (AUC) of iptacopan were not affected by food. Therefore, iptacopanmay be taken with or without food.

Iptacopan showed concentration-dependent plasma protein binding due to binding to the target FB inthe systemic circulation. Iptacopan was 75 to 93% protein bound in vitro at the relevant clinicalplasma concentrations. After administration of iptacopan 200 mg twice daily, the geo-mean apparentvolume of distribution at steady state was approximately 265 litres.

Metabolism is a predominant elimination pathway for iptacopan, with approximately 50% of the doseattributed to oxidative pathways. Metabolism of iptacopan includes N-dealkylation, O-deethylation,oxidation and dehydrogenation, mostly driven by CYP2C8 with a small contribution from CYP2D6.

Direct glucuronidation (by UGT1A1, UGT1A3 and UGT1A8) is a minor pathway. In plasma,iptacopan was the major component, accounting for 83% of the AUC0-48 h. Two acyl glucuronideswere the only metabolites detected in plasma and were minor, accounting for 8% and 5% of the

AUC0-48 h. Iptacopan metabolites are not considered pharmacologically active.

In a study in healthy volunteers, following a single 100 mg oral dose of [14C]-iptacopan, mean totalexcretion of radioactivity (iptacopan and metabolites) was 71.5% in the faeces and 24.8% in the urine.

Specifically, 17.9% of the dose was excreted as parent iptacopan in the urine and 16.8% in faeces. Theapparent clearance (CL/F) after administration of iptacopan 200 mg twice daily at steady state is7 960 ml/h. The half-life (t½) of iptacopan at steady state is approximately 25 hours afteradministration of iptacopan 200 mg twice daily.

At doses between 25 and 100 mg twice daily, the pharmacokinetics of iptacopan were overall less thandose proportional. However, oral doses of 100 mg and 200 mg were approximately dose proportional.

Non-linearity was primarily attributed to the saturable binding of iptacopan to its target FB in plasma.

A dedicated interaction study in which iptacopan was co‑administered with other medicinal productswas conducted in healthy volunteers and did not demonstrate any clinically relevant interactions.

Iptacopan as a substrate

When iptacopan is co‑administered with clopidogrel (a moderate CYP2C8 inhibitor), the iptacopan

Cmax and the AUC increased by 5% and 36%, respectively.

OATP1B1/OATP1B3 inhibitors

When iptacopan is co‑administered with ciclosporin (a strong OATP 1B1/1B3 inhibitor, and a PgPand BCRP inhibitor), the iptacopan Cmax and AUC increased by 41% and 50%, respectively.

Iptacopan as an inhibitor

PgP substrates

In the presence of iptacopan, the Cmax of digoxin (a PgP substrate) increased by 8% while its AUC wasunchanged.

OATP substrates

In the presence of iptacopan, the Cmax and AUC of rosuvastatin (an OATP substrate) remainedunchanged.

A population pharmacokinetic (PK) analysis was conducted on data from 234 patients. Age (18 to84 years), body weight, eGFR, race and gender did not significantly influence iptacopan PK. Studiesthat included Asian subjects showed that the PK of iptacopan were similar to Caucasian (white)subjects.

The effect of renal impairment on the clearance of iptacopan was assessed using a population PKanalysis. There were no clinically relevant differences in the clearance of iptacopan between patientswith normal renal function and patients with mild (eGFR between 60 and 90 ml/min) or moderate(eGFR between 30 and 60 ml/min) renal impairment and no dose adjustment is required (seesection 4.2). Patients with severe renal impairment or on dialysis have not been studied.

Based on a study in subjects with mild (Child-Pugh A, n=8), moderate (Child-Pugh B, n=8) or severe(Child-Pugh C, n=6) hepatic impairment, a negligible effect on the total systemic exposure ofiptacopan was observed compared to subjects with normal hepatic function. Unbound iptacopan Cmaxincreased 1.4-, 1.7- and 2.1-fold, and unbound iptacopan AUCinf increased by 1.5-, 1.6- and 3.7-fold insubjects with mild, moderate and severe hepatic impairment, respectively (see section 4.2).

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproductionand development.

In oral dose animal fertility studies, iptacopan did not impact fertility in male rats up to the highestdose tested (750 mg/kg/day), which corresponds to 6-fold the MRHD based on AUC. Reversibleeffects on the male reproductive system (testicular tubular degeneration and hypospermatogenesis)were observed in repeated dose toxicity studies after oral administration in rats and dogs at doses >3-fold the MRHD based on AUC, with no apparent effects on sperm numbers, morphology or motility,or fertility.

In the female fertility and early embryonic developmental study in rats, iptacopan-related findingswere limited to increased pre-and post-implantation losses and, consequently, decreased numbers oflive embryos only at the highest dose of 1 000 mg/kg/day orally, which corresponds to ~5-fold the

MRHD based on total AUC. The dose of 300 mg/kg/day is the no-observed-adverse-effect level(NOAEL) which corresponds to ~2-fold the MRHD based on AUC.

Animal reproduction studies in rats and rabbits demonstrated that oral administration of iptacopanduring organogenesis did not induce adverse embryo or foetal toxicity up to the highest doses, whichcorrespond to 5-fold (for rats) and 8-fold (for rabbits) the MRHD of 200 mg twice daily based on

AUC.

In the pre- and postnatal development study in rats, with iptacopan administered orally to femalesduring gestation, parturition and lactation (from gestational day 6 to lactation day 21), there were noadverse effects on pregnant dams or offspring up to the highest dose tested of 1 000 mg/kg/day(estimated 5-fold the MRHD based on AUC).

In the chronic toxicity study, one male dog at the highest dose level (margin to clinical exposure near20-fold), was sacrificed 103 days after completed iptacopan administration due to irreversible non-regenerative severe anaemia associated with bone marrow fibrosis. During the treatment phase,haematology findings indicating inflammation and dyserythropoiesis were observed. No mechanismfor the observed findings has been identified and a relation to treatment cannot be excluded.

Iptacopan was not genotoxic or mutagenic in a battery of in vitro and in vivo assays.

Carcinogenicity studies conducted with iptacopan in mice and rats via oral administration did notidentify any carcinogenic potential. The highest doses of iptacopan studied in mice (1 000 mg/kg/day)and rats (750 mg/kg/day) were approximately 4- and 12-fold the MRHD based on AUC, respectively.

In vitro and in vivo phototoxicity tests were equivocal. In the in vivo phototoxicity study, withiptacopan at doses between 100 and 1 000 mg/kg (equivalent to 38-fold the human total Cmax at the

MRHD), some mice showed a non-dose-response pattern of transient minimal erythema, scabs anddryness and slight increase in average ear weight subsequent to irradiation.

Gelatin

Red iron oxide (E172)

Titanium dioxide (E171)

Yellow iron oxide (E172)

Black iron oxide (E172)

Concentrated ammonia solution (E527)

Potassium hydroxide (E525)

Propylene glycol (E1520)

Shellac (E904)

Not applicable.

3 years.

This medicinal product does not require any special storage conditions.

FABHALTA is supplied in PVC/PE/PVDC blisters with aluminium foil backing.

Packs containing 28 or 56 hard capsules.

Multipacks containing 168 (3 packs of 56) hard capsules.

Not all pack sizes may be marketed.

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

Novartis Europharm Limited

Vista Building

Elm Park, Merrion Road

Dublin 4

Ireland

EU/1/24/1802/001-003

17 May 2024

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

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