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

Adapted from Peffault de Latour R, et al. 2024.³

*Eculizumab or ravulizumab.^1–3
†n=1 discontinued due to pregnancy.^1,4
‡n=1 did not enter extension period; investigator decision.^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.¹
**Throughout the study.³

Primary endpoints

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:^1,3

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

• Hb normalisation (Hb ≥12 g/dL) rate

Response rate of patients achieving a sustained increase of Hb levels ≥2 g/dL from baseline

Image

82.3% (n=51/60)^† of patients treated with FABHALTA® demonstrated Hb improvements (sustained increase of Hb levels ≥2 g/dL) vs 2% (n=0/35)^† with C5i (difference between arms = 80.2%; 95% CI: 71.2% to 87.6%; p<0.0001).^1,3

 

Adapted from FABHALTA® Summary of Product Characteristics and Peffault de Latour R, et al. 2024.^1,3

Response rate of patients achieving a sustained Hb level ≥12 g/dL

Image

68.8% (n=42/60)^† of patients treated with FABHALTA® achieved ≥12 g/dL vs 1.8% (n=0/35)^† with C5i (difference between arms = 67.0%; 95% CI: 56.4% to 76.9%; p<0.0001).^1,3

 

Adapted from FABHALTA® Summary of Product Characteristics and Peffault de Latour R, et al. 2024.^1,3

*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
†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.^1,3

Secondary endpoint: transfusion avoidance¹

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).¹

Transfusion avoidance rate achieved by Week 24^†1

48-week data: transfusion avoidance⁴

Transfusion avoidance rates observed at Week 24 were maintained with FABHALTA® up to Week 48, with benefit also observed after switching from C5i at Week 24.^‡4

>90% of patients in the FABHALTA® and C5i-FABHALTA® arms were observed to avoid RBC transfusions by Week 48.^§4

Observed percentage of patients who avoided RBC transfusion^†‡¶4

*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

†Transfusion independence is defined as absence of administration of packed-RBC transfusions or meeting the criteria for transfusion between Days 14 and 168.^1

‡Assessment of transfusion avoidance did not include the first 2 weeks after initiation of FABHALTA® monotherapy.^4

§Defined as neither receiving nor meeting the criteria for administration of an RBC transfusion.^4

¶The patient numbers are observed data, and the percentages were calculated directly from these (i.e. these are descriptive statistics, not estimated proportions as were used in the primary 24-week analysis).⁴

Secondary endpoint: change from baseline in Hb levels³

With FABHALTA®, increases in Hb were observed as early as Week 2 and sustained for 24 weeks vs C5i.³

Mean Hb levels from baseline to Week 24*³

Adapted from Peffault de Latour R, et al. 2024.³

48-week data: change from baseline in Hb levels⁴

Hb levels were maintained to Week 48 in the FABHALTA® arm and a level of 12 g/dL was achieved by Week 28 in the treatment switch arm.⁴

Table adapted from Risitano AM, et al. 2023.⁴

C5i to FABHALTA® switch

 Adapted from Risitano AM, 2023.⁴

*Includes values within 30 days of RBC transfusion. 3/62 patients in the FABHALTA® arm and 21/35 patients in the C5i arm had RBC transfusions between Days 14 and 168.^3

†Change from baseline was analysed using a mixed model of repeated measures that adjusted for covariates, including baseline Hb. Analysis includes all central laboratory Hb data, including post-transfusion data.^4
‡Includes post-transfusion data.^4 
§At Week 25, Hb data were only available for one patient in the FABHALTA® arm (Hb level: 13.9 g/dL); this was not a scheduled visit in the protocol for the FABHALTA® arm but was for the C5i-FABHALTA® arm. The value in the FABHALTA® arm is not plotted on the graph as one patient cannot be representative of the whole treatment group.⁴

Secondary endpoint: FACIT-Fatigue scores³

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

Mean FACIT-Fatigue scores over 24 weeks*³

Adapted from Peffault de Latour R, et al. 2024.³

(Adjusted mean change from baseline FABHALTA® +8.6; 95% CI: 6.7, 10.5; C5i +0.3; 95% CI: -2.2, 2.8; difference between arms +8.29; 95% CI: 5.28, 11.29; p<0.0001).^‡1,3

48-week data: FACIT-Fatigue scores⁴

A reduction in patient-reported fatigue was achieved within 4 weeks in patients who switched from C5i to FABHALTA®.⁴

Table adapted from Risitano AM, et al. 2023.⁴

C5i to FABHALTA® switch

Adapted from Risitano AM, et al. 2023.⁴

*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 0 being the worst possible score and 52 being the best possible score indicating no fatigue.^5

†Determined through the assessment of 1010 adults in the US in the 1990s and 2426 adults in Germany in 2015.^5

‡Adjusted mean assessed between Days 126 and 168, values within 30 days after transfusion were included in the analysis.^1
§Change from baseline was analysed using a mixed model of repeated measures that adjusted for covariates, including baseline FACIT-Fatigue score.⁴

Secondary endpoint: LDH improvement (<1.5 x ULN)¹

FABHALTA® may offer haemolysis control by helping to reduce ARC vs C5i.¹

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

Image

Image

 

 No statistical difference with FABHALTA® vs C5i (95% CI: 0.89, 1.10; p=0.84).¹

Mean LDH level from baseline to Week 24³ 

Adapted from Peffault de Latour R, et al. 2024.³

*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

48-week data: LDH improvement (<1.5 x ULN)⁴

Mean LDH levels were generally maintained at <1.5 x ULN in both treatment arms up to Week 48.⁴

Mean LDH levels were generally consistent with baseline levels and levels at Week 24 in both treatment arms.⁴

C5i to FABHALTA® switch

Adapted from Risitano AM, et al. 2023.⁴

^‡At Week 25, LDH data were only available for one patient in the FABHALTA® arm (LDH level: 348.0 U/L); this was not a scheduled visit in the protocol for the FABHALTA® arm but was for the C5i-FABHALTA® arm. The value in the FABHALTA® arm is not plotted on the graph as one patient cannot be representative of the whole treatment group.^4
§Variability in LDH level in the FABHALTA® arm at Week 48 was driven by a few outliers.⁴

Secondary endpoint: ARC improvement^1,3

Superior reductions in ARC with FABHALTA® vs C5i¹

Adapted from FABHALTA® Summary of Product Characteristics and Peffault de Latour R, et al. 2024.^1,3

*Assessed between Days 126 and 168, values within 30 days after transfusion were included in the analysis.¹

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

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

Mean ARC from baseline to Week 24³

(Difference between arms, in adjusted mean change from baseline −116.2 x 10⁹/L; 95% CI: −132.0, −100.3; p<0.001).³

Adapted from Peffault de Latour R, et al. 2024 supplementary appendix.³

48-week data: ARC improvement⁴

A reduction in mean ARC to within the normal range (13.5 x 10⁹/L to 123 x 10⁹/L)³ was maintained to Week 48 in the FABHALTA® arm and was achieved by Week 25 in the C5i-FABHALTA® arm.⁴

C5i to FABHALTA® switch

Adapted from Risitano AM, et al. 2023.⁴

^¶At Week 25, ARC data were only available for one patient in the FABHALTA® arm (ARC: 76.00 × 10⁹/L); this was not a scheduled visit in the protocol for the FABHALTA® arm but was for the C5i-FABHALTA® arm. The value in the FABHALTA® arm is not plotted on the graph as one patient cannot be representative of the whole treatment group.⁴

Secondary endpoint: occurrence of clinical BTH*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

Annualised rate of BTH

Adapted from FABHALTA® Summary of Product Characteristics.¹

48-week data: occurrence of clinical BTH⁴

The number of clinical BTH events reduced after switching from C5i to FABHALTA®.⁴

The overall adjusted annualised rate of clinical BTH^‡ since initiation of FABHALTA®, including patients in both treatment arms, was 0.11 (95% CI: 0.05, 0.23).⁴

Patients with clinical BTH between Week 1–Week 48

Adapted from Risitano AM, et al. 2023.⁴

All clinical BTH events^‡ reported during FABHALTA® monotherapy in APPLY-PNH were mild or moderate in severity and resolved without discontinuation.^‖**⁴

*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.^3 
‡Events that met the prespecified criteria in the protocol for clinical BTH. All haemolytic events were also reported as treatment-emergent adverse events (TEAEs), irrespective of whether they met the criteria for clinical BTH.^4
§One of the patients in the FABHALTA® arm had an event of clinical BTH in the randomised treatment period and a second event of clinical BTH in the extension period. Therefore, overall, six of 62 patients in the FABHALTA® arm had clinical BTH.^4 
¶Of 62 patients in the FABHALTA® arm, 61 entered the extension period.^4 
‖Of 35 patients who were randomised to the C5i arm, 34 switched to FABHALTA® monotherapy in the extension period. The patient who had clinical BTH after switching to FABHALTA® did not have clinical BTH during C5i treatment in the randomised treatment period.⁴  
**One patient received a single dose of eculizumab per the decision of their investigator.⁴ 

FABHALTA® is generally well tolerated.^1,3,4

Adapted from FABHALTA® Summary of Product Characteristics,¹ Peffault de Latour R, et al. 2024,³ and Risitano AM, et al. 2023.⁴

• The most commonly reported adverse reactions in adult patients with PNH were upper respiratory tract infection (18.9%), headache (18.3%) and diarrhoea (11.0%). The most commonly reported serious adverse reaction was urinary tract infection (1.2%)¹

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

• 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 amount 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 meningococcal or pneumococcal infections were reported in the APPLY-PNH trial. One patient had a serious UTI caused by Pseudomonas aeruginosa, an encapsulated bacterium, in the FABHALTA® group.³ Please refer to the vaccinations section of the SmPC for additional information prior to prescription

• Urinary tract infection (UTI) was the most commonly reported serious AE¹

See the SmPC for full safety information and detailed information on drug–drug interactions.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
†During 24 weeks, 2/62 patients experienced clinical BTH with FABHALTA® vs 6/35 with C5i (assessed between Days 1 and 168).³

APPOINT-PNH was a 24-week multicentre, single-arm, open-label Phase III study designed to investigate the efficacy and safety of FABHALTA® in treating patients with PNH who have not received treatment previously with C5is.^1,3,8

Adapted from Peffault de Latour R, et al. 2024 supplementary appendix.³

*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.^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.^1
‖Throughout the study.³

Primary endpoint

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

Response rate of patients achieving a sustained increase of Hb levels ≥2 g/dL from baseline

Adapted from FABHALTA® Summary of Product Characteristics and Novartis Data on File. 2022.^1,9  

Seven patients had partially missing central Hb data between Days 126 and 168. The haematological response was derived using multiple imputation.¹

The secondary endpoint of Hb improvement ≥12 g/dL from baseline (8.2 g/dL) was observed in 62.8% (n=19/33) of patients treated with FABHALTA®.¹

Response rate of patients achieving a sustained Hb level ≥12 g/dL

Adapted from FABHALTA® Summary of Product Characteristics.¹

Seven patients had partially missing central Hb data between Days 126 and 168. The haematological response was derived using multiple imputation.¹

48-week data

The percentage of patients with ≥2 g/dL increase in Hb level from baseline (8.2 g/dL)¹ (irrespective of RBC transfusions) was maintained at Week 48 (97.4%; n=38/39) from Week 24 (94.9%; n=37/39).*^†10 

Percentage of patients with ≥2 g/dL increase in Hb level from baseline

Adapted from Risitano AM, et al. 2024.¹⁰

A numerically higher proportion of patients achieved Hb ≥12 g/dL (irrespective of RBC transfusions) at Week 48 (79.5%; n=31/39) than at Week 24 (66.7%; n=26/39).*^†10

Percentage of patients with ≥12 g/dL increase in Hb level from baseline

Adapted from Risitano AM, et al. 2024.¹⁰

Hb levels were maintained from Week 24.¹⁰

Mean Hb level (SD) over time during the 48-week treatment period of APPOINT-PNH:^†§10

Adapted from Risitano AM, et al. 2024.¹⁰

*39 patients had non-missing data.^10

†Includes post-transfusion data. Only one patient required RBC transfusions between Weeks 2 and 48.^10
‡The patient numbers are observed data, and the percentages were calculated directly from these (i.e., these are descriptive statistics, not estimated proportions as were used in the primary 24-week analysis).^10
§Mean (SD) baseline Hb level was 8.16 (1.09) g/dL.¹⁰

Secondary endpoint: transfusion avoidance¹

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

70% of patients (n=40) had at least one RBC transfusion in the 6 months prior to treatment.¹

48-week data: transfusion avoidance¹⁰

FABHALTA® transfusion rates observed at Week 24 were maintained through to Week 48.¹⁰

Maintained transfusion avoidance in 39/40 (97.5%) patients^§ (95% CI: 92.5–100.0 [estimated proportions from observed data]).^¶10

*Based on observed data among evaluable patients. In 7 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
†Response rate reflects the model-estimated proportion.^1
‡Transfusion avoidance is defined as absence of administration of packed-RBC transfusions or meeting the criteria for transfusion between Days 14 and 168.^1
§Patients not receiving or not requiring transfusions in the specified time period.^10
¶Estimated proportions reflect the probability of meeting the endpoint criteria among the study population. The estimated proportion for Weeks 2 to 48 was computed using simple proportion, based on observed data. The 48-week analyses did not consider any imputation framework and were based on actual transfusions or transfusion criteria being met. The 95% CIs were obtained using the bootstrap method.¹⁰

Secondary endpoint: FACIT-Fatigue scores³

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

Mean FACIT-Fatigue scores over 24 weeks*³

Adapted from Peffault de Latour R, et al. 2024.³

Adjusted mean change from baseline with FABHALTA® +10.75; 95% CI: 8.66–12.84.^‡11

48-week data: FACIT-Fatigue scores¹⁰

Changes in patient-reported fatigue were maintained from baseline to Week 48.¹⁰

Mean FACIT-Fatigue scores over time during the 48-week treatment period of APPOINT-PNH¹⁰

Adapted from Risitano AM, et al. 2024.¹⁰

No statistical testing was performed so conclusions cannot be made from this data.

*The 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 0 being the worst possible score and 52 being the best possible score indicating no fatigue.^5
†Determined through the assessment of 1010 adults in the US in the 1990s and 2426 adults in Germany in 2015.^5
‡Between Days 126 and 168.¹¹

Secondary endpoint: LDH improvement (<1.5 x ULN)

FABHALTA® may offer haemolysis control by reducing LDH and ARC from baseline.^1,3

95% of patients had LDH ≤1.5 × ULN at Week 24.³

Adapted from FABHALTA® Summary of Product Characteristics and Peffault de Latour R, et al. 2024.^1,3

*Adjusted mean assessed between Days 126 and 168, values within 30 days after transfusion were included in the analysis.¹  

Reductions in LDH were observed from Week 2 and sustained up to 24 weeks, with 95% of patients achieving LDH ≤1.5 x ULN at Week 24.^1,3
(Adjusted mean LDH change from baseline: –83.6% [95% CI: –84.9, –82.1]).¹

Mean LDH level from baseline to Week 24³

Adapted from Peffault de Latour R, et al. 2024.³

48-week data: LDH improvement (<1.5 x ULN)

Reductions in LDH were maintained throughout the extension period.¹⁰

Median LDH levels (IQR) over time during the 48-week treatment period of APPOINT-PNH:^†‡10 

Adapted from Risitano AM, et al. 2024.¹⁰

^†Median (IQR) baseline LDH level was 1581.5 (1144.5 to 2054.5) U/L.^10
‡ Variability in LDH level at Week 48 was mainly driven by one outlier.¹⁰

Secondary endpoint: ARC reduction

Adapted from FABHALTA® Summary of Product Characteristics and Peffault de Latour R, et al. 2024.^1,3

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

Mean ARC from baseline to Week 24³

Adapted from Peffault de Latour R, et al. 2024 supplementary appendix.³

*Adjusted mean assessed between Days 126 and 168, values within 30 days after transfusion were included in the analysis.¹

48-week data: ARC reduction

Reductions in ARC were maintained throughout the extension period.^10,12

Median ARC from baseline to Week 48 of APPOINT-PNH:^§10,12

Adapted from Risitano AM, et al. 2025.¹²

^§Dashed lines show the LLN and ULN for ARC (13.5 and 123.0 x 10⁹ cells per L, respectively).¹²

FABHALTA® is generally well tolerated.^1,3,10,12

Adapted from Peffault de Latour R, et al. 2024,3 Risitano AM, et al. 202410 and Risitano AM, et al. 2025.¹²

• The most frequently reported TEAEs (>10% of patients) on FABHALTA® were headache (28%), COVID-19 (15%), and upper respiratory tract infection (13%)³

• The most commonly reported adverse events in the extension period were headache (30%), COVID-19 (22.5%), upper respiratory tract infection (17.5%) and diarrhoea (15.0%). Eight patients (20.0%) experienced at least one serious TEAE¹⁰

• No deaths were observed. One patient experienced a serious encapsulated bacterial infection.^3‡ Please refer to the vaccinations section in the SmPC for additional information prior to prescription

• No patients discontinued due to adverse events³

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

*Upper respiratory tract infection and nasopharyngitis combined.^12
†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.^3,12

Infections
In PNH clinical studies, 1/164 (0.6%) patients with PNH reported serious bacterial pneumonia while receiving treatment with FABHALTA®; the patient had been vaccinated against Neisseria meningitidis, Streptococcus pneumoniae and Haemophilus influenzae type B and recovered following treatment with antibiotics while continuing treatment with FABHALTA®.

Platelet count decreased
Decrease  in platelet count events was reported in 12/164 (7%) patients with PNH. Of these, 5 patients had events of mild severity, 5 had moderate events and 2 had severe events. Patients with severe events had concurrent anti-platelet antibodies or idiopathic bone marrow aplasia with pre-existing thrombocytopenia. The events started within the first 2 months of FABHALTA® 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%) patients had recovered or events were resolving and FABHALTA® treatment was continued throughout in all patients.

Blood cholesterol and blood pressure increases
In patients treated with FABHALTA® 200 mg twice a day in PNH clinical studies, mean increases from baseline of approximately 0.7 mmol/l were seen at Month 6 for total cholesterol and low-density lipoprotein cholesterol (LDL-C). The mean values remained within the normal ranges. Increases in blood pressure, particularly diastolic blood pressure (DBP), were observed (mean increase 4.7 mmHg at Month 6). The mean DBP did not exceed 80 mmHg. Total cholesterol, LDL-C and DBP increases correlated with increases in haemoglobin (Hb) (improvement in anaemia) in patients with PNH.

Heart rate decrease
In patients treated with FABHALTA® 200 mg twice a day in PNH clinical studies, a mean decrease in heart rate of approximately 5 bpm was seen at Month 6 (mean of 68 bpm).