Drug Trials Snapshot: FABHLATA
HOW TO USE THIS SNAPSHOT
The information provided in Snapshots highlights who participated in the key clinical trials that supported the original FDA approval of this drug, and whether there were differences among sex, race, age, and ethnic groups. The “MORE INFO” bar shows more detailed, technical content for each section. The Snapshot is intended as one tool for consumers to use when discussing the risks and benefits of the drugs.
LIMITATIONS OF THIS SNAPSHOT
Do not rely on Snapshots to make decisions regarding medical care. Always speak to your healthcare provider about the benefits and risks of a drug.
Some of the information in this Snapshot is for presentation purposes and does not represent the approved conditions of use of this drug. Refer to the FABHALTA Prescribing Information for all the approved conditions of use of this drug (e.g., indication(s), population(s), dosing regimen(s), safety information).
Snapshots are limited to the information available at the time of the original approval of the drug and do not provide information on who participated in clinical trials that supported later approvals for additional uses of the drug (if applicable).
FABHALTA (iptacopan)
fab hal’ tah
Novartis Pharmaceuticals Corporation
Original Approval date: December 5, 2023
DRUG TRIALS SNAPSHOT SUMMARY:
What is the drug for?
FABHALTA is a prescription drug that is a complement factor B inhibitor, indicated for the treatment of adults with paroxysmal nocturnal hemoglobinuria (PNH).
How is this drug used?
FABHALTA is an oral capsule that is taken twice daily.
Who participated in the clinical trials?
The FDA approved FABHALTA based on evidence from two main clinical trials, APPLY-PNH and APPOINT-PNH, in 137 subjects with PNH. The trials were conducted at 55 sites in 15 countries including Brazil, China, Czech Republic, France, Germany, Italy, Japan, Malaysia, Netherlands, Republic of Korea, Singapore, Spain, Taiwan, United Kingdom, and the United States.
There were 8 subjects included in the APPLY-PNH trial from the United States (no subjects from the United States were included in the APPOINT-PNH trial), and 129 subjects were included from sites outside of the United States. The same trials were used to assess efficacy and safety.
How were the trials designed?
FABHALTA was evaluated in two main clinical trials of subjects with PNH. One trial, APPLY-PNH, was a multi-center, open-label, 24-week, active comparator-controlled trial in adults with PNH on treatment with a stable regimen of an anti-C5 treatment (either eculizumab or ravulizumab) for at least six months. Ninety-seven subjects were randomized to switch to FABHALTA or to continue anti-C5 treatment. The second trial, APPOINT-PNH, was a single-arm study in adults with PNH who were not previously treated with a complement inhibitor. The primary endpoint for both trials was an increase in hemoglobin levels from baseline in the absence of red blood cell (RBC) transfusions.
How were the trials designed?
The safety and efficacy of FABHALTA were established in two main clinical trials, APPLY-PNH and APPOINT-PNH, in 137 subjects with PNH.
The APPLY-PNH trial was a multicenter, international, randomized, open-label, active comparator-controlled study in subjects with PNH and residual anemia (hemoglobin <10 g/dL) despite prior anti-C5 treatment (eculizumab or ravulizumab). Subjects were randomized in an 8:5 ratio to receive either FABHALTA 200 mg orally twice daily or to continue anti-C5 treatment throughout the duration of the 24-week randomized control period. The dose of eculizumab or ravulizumab was continued at the subject’s current dosing regimen prior to study entry, which was consistent with the U.S. approved prescribing for each product. There were two primary endpoints: (1) proportion of subjects achieving a sustained increase in hemoglobin levels from baseline ≥2 g/dL between Day 126 (Week 18) and Day 168 (Week 24) in the absence of transfusions between Day 14 and Day 168; and (2) proportion of subjects achieving sustained hemoglobin levels ≥12 g/dL between Day 126 and Day 168 in the absence of transfusions between Day 14 and Day 168.
The APPOINT-PNH trial was a multicenter, single-arm, open-label trial in adult subjects with PNH who were naïve to complement inhibitor therapy and had hemolytic anemia (hemoglobin <10 g/dL and lactate dehydrogenase [LDH] >1.5 times the upper limit of normal [ULN]). The study consisted of 24 weeks. The primary endpoint was the proportion of subjects achieving a sustained increase from baseline in hemoglobin levels of ≥2 g/dL assessed in the absence of RBC transfusions.
DEMOGRAPHICS SNAPSHOT
Figure 1 summarizes how many male and female patients were enrolled in the combined clinical trials used to evaluate the efficacy of FABHALTA.
Figure 1. Baseline Demographics by Sex
Source: Adapted from FDA Review
Figure 2 summarizes how many patients by race were enrolled in the combined trials used to evaluate the side effects of FABHALTA.
Figure 2. Baseline Demographics by Race
Source: Adapted from FDA Review
Figure 3 summarizes how many patients by age were enrolled in the combined trials used to evaluate the side effects of FABHALTA.
Figure 3. Baseline Demographics by Age
Source: Adapted from FDA Review
Figure 4 summarizes how many patients by ethnicity were enrolled in the combined trials used to evaluate the side effects of FABHALTA.
Figure 4. Baseline Demographics by Ethnicity
Source: Adapted from FDA Review
Who participated in the trials?
Table 1. Baseline Demographics, Safety Population, Trials APPLY-PNH and APPOINT-PNH
| APPLY-PNH | APPOINT-ONH | Pooled Trials | ||
| FABHALTA | Anti-C5 | FABHALTA | FABHALTA Total | |
| Characteristic | N=62 | N=35 | N=40 | N=102 |
| Sex, n (%) | ||||
| Female | 43 (69.4) | 24 (68.6) | 17 (42.5) | 60 (58.8) |
| Male | 19 (30.6) | 11 (31.4) | 23 (57.5) | 42 (41.2) |
| Age, years | ||||
| Mean (SD) | 51.7 (16.94) | 49.8 (16.69) | 42.1 (15.85) | 47.9 (17.1) |
| Median (min, max) | 53.0 (22.0, 84.0) | 45.0 (20.0, 82.0) | 38.5 (18.0, 81.0) | 47.0 (18.0, 84.0) |
| Age group, years, n (%) | ||||
| 18 to <65 | 44 (71.0) | 27 (77.1) | 37 (92.5) | 81 (79.4) |
| 65 to <75 | 12 (19.4) | 7 (20.0) | 2 (5.0) | 14 (13.7) |
| ≥75 | 6 (9.7) | 1 (2.9) | 1 (2.5) | 7 (6.9) |
| Race, n (%) | ||||
| Asian | 12 (19.4) | 7 (20.0) | 27 (67.5) | 39 (38.2) |
| Black or African American | 2 (3.2) | 2 (5.7) | 1 (2.5) | 3 (2.9) |
| White | 48 (77.4) | 26 (74.3) | 12 (30.0) | 60 (58.8) |
| Ethnicity, n (%) | ||||
| Hispanic or Latino | 8 (12.9) | 2 (5.7) | 2 (5.0) | 10 (9.8) |
| Not Hispanic or Latino | 51 (82.3) | 27 (77.1) | 35 (87.5) | 86 (84.3) |
| Not reported | 2 (3.2) | 6 (17.1) | 2 (5.0) | 4 (3.9) |
| Unknown | 1 (1.6) | 0 (0) | 1 (2.5) | 2 (2.0) |
| Country of participation, n (%) | ||||
| Brazil | 2 (3.2) | 2 (5.7) | - | 2 (2.0) |
| China | - | - | 20 (50) | 20 (19.6) |
| Czech Republic | 1 (1.6) | 0 (0) | - | 1 (1.0) |
| Germany | 13 (21.0) | 7 (20.0) | 4 (10) | 17 (16.7) |
| Spain | 3 (4.8) | 1 (2.9) | - | 3 (2.9) |
| France | 9 (14.5) | 6 (17.1) | 4 (10) | 13 (12.7) |
| United Kingdom | 5 (8.1) | 6 (17.1) | 4 (10) | 9 (8.8) |
| Italy | 12 (19.4) | 5 (14.3) | 2 (5) | 14 (13.7) |
| Japan | 6 (9.7) | 3 (8.6) | - | 6 (5.9) |
| Republic of Korea | 1 (1.6) | 0 (0) | 2 (5) | 3 (2.9) |
| Malaysia | - | - | 3 (7.5) | 3 (2.9) |
| Netherlands | 2 (3.2) | 2 (5.7) | - | 2 (2.0) |
| Singapore | - | - | 1 (2.55) | 1 (1.0) |
| Taiwan | 2 (3.2) | 1 (2.9) | - | 2 (2.0) |
| United States | 6 (9.7) | 2 (5.7) | - | 6 (5.9) |
Source: Adapted from FDA Review
What are the benefits of this drug?
One trial in adults with PNH and residual anemia (hemoglobin <10 g/dL) despite previous treatment with a stable regimen of anti-C5 treatment (either eculizumab or ravulizumab) for at least six months, demonstrated that switching to FABHALTA was better compared to continuing on anti-C5 therapy in achieving an increase of ≥2 g/dL in hemoglobin from baseline (hemoglobin improvement) and sustaining hemoglobin levels ≥12 g/dL after 24 weeks of treatment, without the need for RBC transfusion. In the second trial in adults with PNH who were not previously treated with a complement inhibitor, patients achieved an increase in hemoglobin levels from baseline of ≥2 g/dL in the absence of RBC transfusions.
What are the benefits of this drug (results of trials used to assess efficacy)?
APPLY-PNH was an open-label, 24-week, active comparator-controlled trial which enrolled adults with PNH and residual anemia (hemoglobin <10 g/dL) despite previous treatment with a stable regimen of anti-C5 treatment (either eculizumab or ravulizumab) for at least six months prior to randomization. Ninety-seven subjects were randomized in an 8:5 ratio to switch to FABHALTA 200 mg orally twice daily (n=62) or to continue anti-C5 treatment (U.S.-approved and non-U.S.-approved eculizumab product, n=23; or U.S.-approved and non-U.S.-approved ravulizumab product, n=12) throughout the duration of the 24-week randomized controlled period. The benefit of the drug was based upon the demonstration of superiority of switching to FABHALTA compared to continuing on anti-C5 therapy in achieving hematological response after 24 weeks of treatment, without a need for RBC transfusion, by assessing the proportion of patients demonstrating: (1) sustained increase of ≥2 g/dL in hemoglobin levels from baseline (hemoglobin improvement) (82.3% versus 0%, respectively, p<0.0001 [95% CI: 71.6%, 91.4%)]; and (2) sustained hemoglobin levels ≥12 g/dL (67.7% versus 0%, p<0.0001 [95% CI: 54.6%, 78.6%)].
APPOINT-PNH was a single arm trial in adults with PNH who were not previously treated with a complement inhibitor. This study enrolled a total of 40 adults with PNH (RBC clone size ≥10%), hemoglobin <10 g/dL, and LDH >1.5 times ULN. All 40 patients received FABHALTA 200 mg orally twice daily during the 24-week treatment period. In total, 77.5% (95% CI: 61.5%, 89.2%) of patients (31/40) achieved a sustained increase in hemoglobin levels from baseline of ≥2 g/dL in the absence of RBC transfusions.
Table 2. Efficacy Results for Clinical Trials APPLY-PNH and APPOINT-PNH
| APPLY-PNH | APPLY-PNH | ||
| FABHALTA | Anti-C5a | FABHALTA | |
| Efficacy Endpoint | N=62 | N=35 | N=40 |
| Patients with sustained increase of hemoglobin levels ≥2 g/dL from baseline in the absence of transfusions, n/N | 51/62 | 0/35 | 31/40 |
| Response rate % (95% CI) | 82.3 (70.5, 90.8) | 0 (0, 10) | 77.5 (61.5, 89.2) |
| Patients with sustained hemoglobin level ≥12 g/dL in the absence of transfusions, n/N | 42/62 | 0/35 | - |
| Response rate % (95% CI) | 67.7 (54.7, 79.1) | 0 (0, 10) | - |
Source: Adapted from FABHALTA Prescribing Information
a Anti-C5 treatment consisted of either eculizumab or ravulizumab
Abbreviations: CI, confidence interval; n, number of patients meeting criteria; N, number of patients in treatment arm
Were there any differences in how well the drug worked in clinical trials among sex, race, and age?
- Sex: FABHALTA worked similarly in males and females*.*
- Race: The number of patients of races other than White was small; therefore, differences in how FABHALTA worked among races could not be determined.
- Age: FABHALTA worked similarly in patients younger and older than 45 years of age.
Were there any differences in how well the drug worked in clinical trials among sex, race, and age groups?
The subgroup analysis by sex and age were similar for the efficacy of FABHALTA. The number of Asian and Black or African American subjects were small and therefore the differences in how FABHALTA worked among races could not be compared. The number of Hispanic or Latino subjects was also small and therefore the differences in how FABHALTA worked among ethnicities could not be compared.
Table 3, Table 4, and Table 5 summarize efficacy results by sex, race, age, and ethnicity based on primary endpoints in Trials APPLY-PNH and APPOINT-PNH.
Table 3. Subgroup Analyses for the Primary Endpoint of ≥2 g/dL Increase in Hb From Baseline, Trial APPLY-PNH
| FABHALTA, N=62 | Anti-C5, N=35 | Treatment Difference | |||
| Subgroup | n/NS (%) | 95% CI | n/NS (%) | 95% CI | % (95% CI) |
| Overall | 51/62 (82.3) | 70.5, 90.8 | 0/35 (0.0) | 0.0, 10.0 | 81.5 (71.6, 91.4) |
| Sex | |||||
| Male | 15/19 (78.9) | 54.4, 93.9 | 0/11 (0.0) | 0.0, 28.5 | 75.6 (54.8, 96.4) |
| Female | 36/43 (83.7) | 69.3, 93.2 | 0/24 (0.0) | 0.0, 14.2 | 83.3 (72.0, 94.6) |
| Age, years | |||||
| <45 | 20/25 (80.0) | 59.3, 93.2 | 0/16 (0.0) | 0.0, 20.6 | 83.2 (69.7, 96.7) |
| ≥45 | 31/37 (83.8) | 68.0, 93.8 | 0/19 (0.0) | 0.0, 17.6 | 84.9 (72.8, 97.1) |
| Race | |||||
| Asian | 10/12 (83.3) | 51.6, 97.9 | 0/7 (0.0) | 0.0, 41.0 | 80.1 (55.4, 100.0) |
| Black or African American | 0/2 (0.0) | NA | 0/2 (0.0) | NA | NA |
| White | 41/46 (85.4) | 72.2, 93.9 | 0/26 (0.0) | 0.0, 13.2 | 84.9 (74.5, 95.3) |
| Ethnicity | |||||
| Hispanic or Latino | 7/8 (87.5) | 47.3, 99.7 | 0/2 (0.0) | 0.0, 84.2 | 84.2 (55.8, 100.0) |
| Not Hispanic or Latino | 42/51 (82.4) | 69.1, 91.6 | 0/27 (0.0) | 0.0, 12.8 | 81.9 (71.1, 92.6) |
| Not reported | 2/2 (100.0) | 15.8, 100.0 | 0/6 (0.0) | 0.0, 45.9 | 100.0 (100.0, 100.0) |
| Unknown | 0/1 (0.0) | NA | NA | NA | NA |
Source: Adapted from FDA Review
Abbreviations: CI, confidence interval; N, number of patients in treatment arm; n, number of patients meeting criteria; NA, not applicable; Ns, total number of patients for each specific subgroup and were assigned to that specific arm
Table 4. Subgroup Analyses for the Primary Endpoint of Hb ≥12 g/dL, Trial APPLY-PNH
| FABHALTA, N=62 | Anti-C5, N=35 | Treatment Difference | |||
| Subgroup | n/NS (%) | 95% CI | n/NS (%) | 95% CI | % (95% CI) |
| Overall | 42/62 (67.7) | 54.7, 79.1 | 0/35 (0.0) | 0.0, 10.0 | 66.6 (54.6, 78.6) |
| Sex | |||||
| Male | 12/19 (63.2) | 38.4, 83.7 | 0/11 (0.0) | 0.0, 28.5 | 56.5 (32.2, 80.8) |
| Female | 30/43 (69.8) | 53.9, 82.8 | 0/24 (0.0) | 0.0, 14.2 | 69.2 (55.2, 83.2) |
| Age, years | |||||
| <45 | 16/25 (64.0) | 42.5, 82.0 | 0/16 (0.0) | 0.0, 20.6 | 68.0 (50.3, 85.7) |
| ≥45 | 26/37 (70.3) | 53.0, 84.1 | 0/19 (0.0) | 0.0, 17.6 | 68.9 (52.5, 85.3) |
| Race | |||||
| Asian | 9/12 (75.0) | 42.8, 94.5 | 0/7 (0.0) | 0.0, 41.0 | 70.2 (41.9, 98.4) |
| Black or African American | 0/2 (0.0) | NA | 0/2 (0.0) | NA | NA |
| White | 33/46 (68.8) | 53.7, 81.3 | 0/26 (0.0) | 0.0, 13.2 | 68.4 (54.9, 81.8) |
| Ethnicity | |||||
| Hispanic or Latino | 6/8 (75.0) | 34.9, 96.8 | 0/2 (0.0) | 0.0, 84.2 | 68.4 (32.2, 100.0) |
| Not Hispanic or Latino | 34/51 (66.7) | 52.1, 79.2 | 0/27 (0.0) | 0.0, 12.8 | 66.3 (53.2, 79.4) |
| Not reported | 2/2 (100.0) | 15.8, 100.0 | 0/6 (0.0) | 0.0, 45.9 | 100.0 (100.0, 100.0) |
| Unknown | 0/1 (0.0) | NA | NA | NA | NA |
Source: Adapted from FDA Review
Abbreviations: CI, confidence interval; N, number of patients in treatment arm; n, number of patients meeting criteria; NA, not applicable; Ns, total number of patients for each specific subgroup and were assigned to that specific arm
Table 5. Subgroup Analyses for the Primary Endpoint of ≥2 g/dL Increase in Hb From Baseline, Trial APPOINT-PNH
| FABHALTA, N=40 | ||
| Subgroup | n/Ns(%) | 95% CI |
| Overall | 31/40 (77.5) | 61.5, 89.2 |
| Sex | ||
| Male | 18/23 (78.3) | 56.3, 92.5 |
| Female | 13/17 (76.5) | 50.1, 93.2 |
| Age, years | ||
| <45 | 18/24 (75.0) | 53.3, 90.2 |
| ≥45 | 13/16 (81.3) | 54.4, 96.0 |
| Race | ||
| Asian | 21/27 (77.8) | 57.7, 91.4 |
| Black or African American | 1/1 (100) | 2.5, 100 |
| White | 9/12 (75.0) | 42.8, 94.5 |
| Ethnicity | ||
| Hispanic or Latino | 0/2 (0) | 0, 84.2 |
| Not Hispanic or Latino | 28/35 (80) | 63.1, 91.6 |
| Not reported | 2/2 (100) | 15.8, 100 |
| Unknown | 1/1 (100) | 2.5, 100 |
Source: Adapted from FDA Review
Higher numbers favor FABHALTA.
Abbreviations: CI, confidence interval; N, number of patients in treatment arm; n, number of patients meeting criteria; Ns, total number of patients for each specific subgroup and were assigned to that specific arm
What are the possible side effects?
FABHALTA can cause hyperlipidemia and patients are to be monitored for PNH manifestations after FABHALTA discontinuation for signs of hemolysis. The most common side effects of FABHALTA were headache, nasopharyngitis, diarrhea, abdominal pain, bacterial infection, viral infection, nausea, and rash.
Table 6. Safety Results, Safety Population, Trials APPLY-PNH and APPOINT-PNH
| APPLY-PNH | APPOINT-PNH | ||
| FABHALTA | Anti-C5b | FABHALTA | |
| N=62 | N=35 | N=40 | |
| Adverse Reactionsa | n (%) | n (%) | n (%) |
| Headache | 12 (19) | 1 (3) | 11 (28) |
| Nasopharyngitis | 10 (16) | 6 (17) | 6 (15) |
| Diarrhea | 9 (15) | 2 (6) | 3 (8) |
| Abdominal pain | 9 (15) | 1 (3) | 3 (8) |
| Bacterial infection | 7 (11) | 4 (11) | 2 (5) |
| Nausea | 6 (10) | 1 (3) | 2 (5) |
| Viral infection | 6 (10) | 11 (31) | 7 (18) |
| Arthralgia | 5 (8) | 1 (3) | 0 |
| Thrombocytopenia | 4 (6) | 0 | 0 |
| Dizziness | 4 (6) | 0 | 1 (3) |
| Systemic hypertension | 4 (6) | 0 | 0 |
| Lipid disorder | 4 (6) | 0 | 3 (8) |
| Rash | 2 (3) | 0 | 4 (10) |
Source: Adapted from FABHALTA Prescribing Information
a Adverse reactions that occurred in ≥5% of FABHALTA-treated patients
b Anti-C5 treatment consisted of either eculizumab or ravulizumab
Were there any differences in side effects among sex, race, and age?
- Sex: The occurrence of side effects was similar in males and females.
- Race: The number of patients of races other than White was small; therefore, the occurrence of side effects of FABHALTA could not be determined.
- Age: The occurrence of side effects was similar in patients younger and older than 45 years of age.
Were there any differences in side effects of the clinical trials among sex, race, and age groups?
The safety profile of FABHALTA was similar among sex and age groups. There were not enough Black or African American patients included in the trials to assess a difference in race groups.
Table 7. Side Effects by Sex, Race, Age, and Ethnicity , Safety Population, Trial APPLY-PNH
| FABHALTA | Anti-C5 | ||
| N=62 | N=35 | Risk Difference % | |
| Characteristic | n/NS (%) | n/NS (%) | (95% CI) |
| Sex | |||
| Female | 35/43 (81.4) | 19/24 (79.2) | 2.2 (-17.8, 22.2) |
| Male | 16/19 (84.2) | 9/11 (81.8) | 2.4 (-25.7, 30.5) |
| Age group, years | |||
| <45 | 21/25 (84.0) | 14/16 (87.5) | -3.5 (-25.2, 18.2) |
| ≥45 | 30/37 (81.1) | 14/19 (73.7) | 7.4 (-16.1, 30.9) |
| Race | |||
| Asian | 10/12 (83.3) | 6/7 (85.7) | -2.4 (-35.8, 31.0) |
| Black or African American | 1/2 (50.0) | 2/2 (100) | -50.0 (-119.3, 19.3) |
| White | 40/48 (83.3) | 20/26 (76.9) | 6.4 (-12.9, 25.7) |
| Ethnicity | |||
| Hispanic or Latino | 5/8 (62.5) | 2/2 (100) | 2.3 (-11.5, 13.0) |
| Not Hispanic or Latino | 44/51 (86.3) | 21/27 (77.8) | 11.0 (-8.3, 30.7) |
| Not Reported | 1/2 (50.0) | 5/6 (83.3) | -12.7 (-28.0, -2.8) |
| Unknown | 1/1 (100) | 0/0 (NA) | 1.6 (-8.4, 8.6) |
Source: Adapted from FDA Review
Abbreviations: CI, confidence interval; N, number of patients in treatment arm; n, number of patients meeting criteria; Ns, total number of patients for each specific subgroup and were assigned to that specific arm
Table 8. Side Effects by Sex, Race, Age, and Ethnicity , Safety Population, Trial APPOINT-PNH
| FABHALTA | |
| N=40 | |
| Characteristic | n/NS (%) |
| Sex | |
| Female | 15/17 (88.2) |
| Male | 22/23 (95.7) |
| Age group, years | |
| <45 | 22/24 (91.7) |
| ≥45 | 15/16 (93.8) |
| Race | |
| White | 11/12 (91.7) |
| Asian | 25/27 (92.6) |
| Black or African American | 1/1 (100) |
| Ethnicity | |
| Hispanic or Latino | 1/2 (50.0) |
| Not Hispanic or Latino | 33/35 (94.3) |
| Not Reported | 2/2 (100) |
| Unknown | 1/1 (100) |
Source: Adapted from FDA Review
Abbreviations: N, number of patients in treatment arm; n, number of patients meeting criteria; Ns, total number of patients for each specific subgroup and were assigned to that specific arm
GLOSSARY
Clinical Trial: Voluntary research studies conducted in people and designed to answer specific questions about the safety or effectiveness of drugs, vaccines, other therapies, or new ways of using existing treatments.
Comparator: A previously available treatment or placebo used in clinical trials that is compared to the actual drug being tested.
Efficacy: How well the drug achieves the desired response when it is taken as described in a controlled clinical setting, such as during a clinical trial.
Placebo: An inactive substance or “sugar pill” that looks the same as, and is given the same way as, an active drug or treatment being tested. The effects of the active drug or treatment are compared to the effects of the placebo.
Subgroup: A subset of the population studied in a clinical trial. Demographic subsets include sex, race, and age groups.