APPLY-PNH was a 24-week multicentre, randomised, open-label Phase III study designed to investigate the efficacy and safety of FABHALTA® in treating patients with PNH who continued to experience anaemia despite anti-C5 antibody treatment.^1–3

*Eculizumab or ravulizumab.^1,3
†Stratified by prior C5i treatment and RBC transfusions in the preceding 6 months.^1,3
‡Assessed between Days 126 and 168.^3
§Between Days 14 and 168 and neither meeting the criteria for administration of an RBC transfusion nor receiving an RBC transfusion between Days 14 and 168.^3
¶Excluding values within 30 days of RBC transfusion.^3
#Throughout the study.³

Evaluation of efficacy was based on two primary endpoints related to the proportion of participants achieving a haematological response after 24 weeks of treatment (assessed between Days 126 and 168), without a need for RBC transfusion:¹

• Increase from baseline in Hb level by ≥2 g/dL

• Hb normalisation (Hb ≥12 g/dL) rate in the absence of RBC transfusions

82.3% (n=51/60) of patients treated with FABHALTA® achieved sustained increase of ≥2 g/dL in Hb vs 2% (n=0/35) of those treated with C5i (difference between arms = 80.2%; 95% CI: 71.2% to 87.6%; p<0.0001) at Week 24.¹

68.8% (n=42/60) of patients treated with FABHALTA® achieved ≥12 g/dL vs 1.8% (n=0/35) of those treated with C5i (difference between arms = 67.0%; 95% CI: 56.4% to 76.9%; p<0.0001) at Week 24.¹

*Assessed between Days 126 and 168. Estimated proportions of patients were calculated to reflect the population average probability of a patient meeting the endpoint criteria.^3
†Based on observed data among evaluable patients. In 2 patients with partially missing central Hb data between Days 126 and 168, the haematological response could not be established unequivocally. The haematological response was derived using multiple imputation. These patients did not discontinue.¹

Secondary endpoint

Transfusion avoidance may be achieved with FABHALTA®.*¹

More patients achieved transfusion avoidance with FABHALTA® vs C5i (94.8% [n=59/62] vs 25.9% [n=14/35]; difference between arms: 68.9%; 95% CI: 51.4 to 83.9; p<0.0001) at Week 24.¹

37/62 in the FABHALTA® arm and 22/35 in the C5i arm had at least one RBC transfusion in the 12 months prior to trial enrolment.¹
*Transfusion independence is defined as absence of administration of packed-RBC transfusions or meeting the criteria for transfusion between Days 14 and 168.^1
†Based on observed data among evaluable patients. In 2 patients with partially missing central Hb data between Days 126 and 168, the haematological response could not be established unequivocally. The haematological response was derived using multiple imputation. These patients did not discontinue.¹

Secondary endpoint

Change from baseline in Hb levels was a secondary endpoint of the study.¹

FABHALTA® demonstrates increases in Hb as early as Week 2, sustained for 24 weeks, vs C5i.¹

Mean Hb levels from baseline to Week 24*¹

*Includes values within 30 days of RBC transfusion. 2/62 patients in the FABHALTA® arm and 21/35 patients in the C5i arm had RBC transfusions between Days 14 and 168.³

Secondary endpoint

FABHALTA® significantly improves FACIT-Fatigue scores to near-normal vs C5i.^3,4

Adjusted mean change from baseline: FABHALTA® +8.59; 95% CI, 6.72–10.47; C5i +0.31; 95% CI, −2.20–2.81.^‡3

Difference between arms: +8.29; 95% CI, 5.28–11.29; p<0.0001.^‡3

Difference between arms: +8.29; 95% CI, 5.28–11.29; p<0.0001.*³

*The Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-F) is a patient-reported measure that assesses fatigue and its impact upon daily activities and function. Scores on the FACIT-Fatigue scale range from 0 to 52, with higher scores indicating less fatigue and 52 indicating no fatigue.^4
†Determined through the assessment of 1010 adults in the US in 2002 and 2426 adults in Germany in 2018.^4
‡Adjusted mean assessed between Days 126 and 168, values within 30 days after transfusion were included in the analysis.^1,3

Secondary endpoint

LDH ratio to baseline (<1.5 x ULN):¹

Adjusted geometric mean ratio to baseline at Week 24*^†1

0.96 (n=62) with FABHALTA® vs 0.98 (n=35) with C5i

No statistical difference: (95% CI, −10.18–11.32) with FABHALTA® vs C5i (p=0.84).^1,6

Apart from at Week 8, mean LDH level remained <1.5 x ULN in both the FABHALTA® and C5i groups throughout the trial (no significant difference between groups).³

Mean LDH level from baseline to Week 24^1,3

ARC improvement:

Superior reductions in ARC with FABHALTA® vs C5i^1,3

ARC reflects bone marrow function, with levels increased during IVH and EVH.⁷

Difference between arms, –116.2 x 10⁹/L; 95% CI, –132.2, –100.3; p<0.0001).

ARC reduction was seen as early as Week 2 and was sustained over 24 weeks.³

Mean ARC from baseline to Week 24³

*Assessed between Days 126 and 168, values within 30 days after transfusion were included in the analysis.^1
†Difference between arms: ratio=0.99 (95% CI, 0.89–1.10; p=0.84).¹

Secondary endpoint

Occurrence of clinical breakthrough haemolysis (BTH)* was a secondary endpoint of the study.³

At Week 24, clinical BTH occurred in 2 out of 62 (3.2%) patients on FABHALTA® and 6 out of 35 (17.1%) patients on C5i.^1,3

This represents a 90% reduction in annualised rate of clinical BTH (Rate ratio: 0.10; 95% CI: 0.02 to 0.61; p=0.01).^†1

*Clinical BTH was defined as meeting clinical criteria (either decrease of Hb level ≥2 g/dL compared with 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 laboratory criteria (LDH >1.5 x ULN and increased as compared with the last 2 assessments).^1
†A negative binomial model was used for the comparison between treatment arms.¹

FABHALTA® is generally well tolerated.^1,3

*Clinical BTH was defined as meeting clinical criteria (either decrease of Hb level ≥2 g/dL compared with 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 laboratory criteria (LDH >1.5 x ULN and increased as compared with the last 2 assessments).^1
†During 24 weeks, 2/62 patients experienced clinical BTH with FABHALTA® vs 6/35 with C5i (assessed between Days 1 and 168).³

• The most frequently reported adverse events (>10% of patients) on FABHALTA® were headache, diarrhoea and nasopharyngitis³

• During the 24 week treatment period, one patient experienced a transient ischaemic attack in the FABHALTA® arm, which was deemed unrelated to treatment by the investigator (assessed between Days 1 and 168)³

• Some patients experienced decreases in platelet counts. These were generally mild to moderate although more severe decreases were seen in a few patients with pre-existing thrombocytopenia¹

• One patient in the FABHALTA® group discontinued treatment due to pregnancy.³ There are no or limited amounts of data from the use of FABHALTA® in pregnant women. The use of FABHALTA® in pregnant women or women planning to become pregnant may only be considered following a careful assessment of the risk and benefits, if necessary¹

• No patients discontinued FABHALTA® due to adverse events³

• No deaths and no serious encapsulated bacteria infections were observed. Please refer to the vaccinations section for additional information prior to prescription³

• UTI was a commonly reported SAE¹

See the SmPC for full safety information and detailed information on drug–drug interactions.¹

BTH, breakthrough haemolysis; C5i, C5 inhibitor; COVID-19, coronavirus disease; Hb, haemoglobin; LDH, lactate dehydrogenase; MAVE, major adverse vascular event; PNH, paroxysmal nocturnal haemoglobinuria; SAE, serious adverse event; SmPC, Summary of Product Characteristics; ULN, upper limit of normal; UTI, urinary tract infection.

APPOINT-PNH was a 24-week multicentre, single-arm, open-label Phase III study designed to investigate the efficacy and safety of FABHALTA® (iptacopan) in treating patients with PNH who have not received treatment previously with C5 inhibitors.^1,3,8

*Confirmed by two measurements 2 to 8 weeks apart for patients not receiving an RBC transfusion during screening, or by one measurement during the first screening visit for patients receiving an RBC transfusion.^3
†Confirmed by two measurements 2 to 8 weeks apart during screening period.^3
‡Assessed between Days 126 and 168.
^§Between Days 14 and 168 and neither meeting the criteria for administration of an RBC transfusion nor receiving an RBC transfusion between Days 14 and 168.
^¶Excluding values within 30 days of RBC transfusion.
^#As per the protocol definition.
^||Throughout the study.

FABHALTA® demonstrated sustained Hb improvements of ≥2 g/dL from baseline (8.2 g/dL) in the absence of transfusions at Week 24 in 92.2% (n=31/33) of patients.^1,3,9

The secondary endpoint of Hb improvement ≥12 g/dL from baseline was observed in 62.8% (n=19/33) of patients treated with FABHALTA®.¹

7 patients had partially missing central haemoglobin data between Days 126 and 168. The haematological response was derived using multiple imputation.⁹

The increase of Hb from baseline was sustained over 24 weeks:^1,3

Mean Hb levels from baseline to Week 24*³

*Assessed between Days 126 and 168. Estimated proportions of patients were calculated to reflect the population average probability of a patient meeting the endpoint criteria.^3
†Includes values within 30 days of RBC transfusion. RBC transfusions were received by 5/40 patients between Days 1 and 13 and by 0/40 patients between Days 14 and 168.³

Secondary endpoint

Transfusion avoidance may be achieved with FABHALTA®.¹

97.6% (n=40/40) achieved transfusion avoidance by Week 24 (95% CI, 92.5–100.0).*¹

28/40 had at least one RBC transfusion in the 6 months prior to treatment.
*Transfusion avoidance is defined as absence of administration of packed-RBC transfusions or meeting the criteria for transfusion between Days 14 and 168.¹

Secondary endpoint

FABHALTA® demonstrated improvements in FACIT-Fatigue levels from baseline.³

Mean FACIT-Fatigue scores over 24 weeks*³

Adjusted mean change from baseline with FABHALTA® +10.75; 95% CI, 8.66–12.84.^‡3,10

*The Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-F) is a patient-reported measure that assesses fatigue and its impact upon daily activities and function. Scores on the FACIT-Fatigue scale range from 0 to 52, with higher scores indicating less fatigue and 52 indicating no fatigue.^4
†Determined through the assessment of 1010 adults in the US in 2002 and 2426 adults in Germany in 2018.^4
‡Between Days 126 and 168.³

Secondary endpoint

FABHALTA® may offer haemolysis control by reducing LDH and ARC from baseline.¹

LDH (<1.5 x ULN):

95% of patients had LDH ≤1.5 × ULN at Week 24:

Reductions in LDH were seen as early as Week 1, and were sustained over 24 weeks, with 95% of patients achieving LDH ≤1.5 x ULN at Week 24.^1,2
Adjusted mean LDH change from baseline: –83.6% (95% CI: –84.9, –82.1).⁹

Mean LDH level from baseline to Week 24^1,3

ARC reduction:

FABHALTA® reduced ARC from baseline by −82.5% at Week 24:^1,3

ARC reduction was observed with FABHALTA® as early as Week 1, and was sustained over 24 weeks.³

*Assessed between Days 126 and 168.¹

Mean ARC from baseline to Week 24¹

FABHALTA® is generally well tolerated.*^1,3

^†During 24-week core treatment period.^3
‡Clinical BTH was defined as meeting clinical criteria (either decrease of Hb level ≥2 g/dL compared with 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 laboratory criteria (LDH >1.5 x ULN and increased as compared with the last 2 assessments).^1
§Severe treatment-emergent adverse event of lobar pneumonia of bacterial aetiology, for which no causative organism was identified and which resolved with antibiotic treatment.³

• The most frequently reported adverse events (>10% of patients) were upper respiratory tract infections, headache and COVID-19³

• No deaths were observed³

• One patient experienced a serious encapsulated bacteria infection;^|| please refer to the FABHALTA® SmPC for additional information prior to prescription³

• No patients discontinued due to adverse events³

See the SmPC for full safety information and detailed information on drug–drug interactions.¹

BTH, breakthrough haemolysis; COVID-19, coronavirus disease; Hb, haemoglobin; LDH, lactate dehydrogenase; MAVE, major adverse vascular event; PNH, paroxysmal nocturnal haemoglobinuria; SmPC, Summary of Product Characteristics; ULN, upper limit of normal.
*The safety profile of FABHALTA® was established in treatment-naïve patients in the APPOINT-PNH Phase III clinical study; 24-week data shown.^3
||Bacterial pneumonia.³