Long-Term PNH Management: Addressing Treatment Goals Beyond Symptom Control

Dr Patel:
I can remember the excitement surrounding FABHALTA when it was first approved for adults with paroxysmal nocturnal hemoglobinuria based on the phase 3 APPLY and APPOINT study results for the 24-week treatment period.^5,8 It’s the only oral monotherapy for treating adult patients with PNH.^5,12-16

Dr Chand:
At the time of its approval, I think there had been many providers in the hematology field tracking the outcomes of both the APPLY and APPOINT clinical trials.

Dr Patel:
Additionally, I remember thinking how eye-opening the concept of striving for hemoglobin normalization versus hemoglobin improvement as an end point and treatment goal was at the time FABHALTA became available.

Dr Chand:
Exactly. FABHALTA, in many ways, has been an additional and valuable resource in our growing toolbox of PNH therapies.^5,12-16 But long-term results for FABHALTA have been something we hematologists have been eagerly awaiting. As you mentioned, the APPLY and APPOINT clinical trials included a 24-week treatment period.^5,8 So, while we saw initial results in those trials, I think many of us wanted to have longer-term data for FABHALTA because PNH is a chronic disease that requires lifelong therapy.^1,2

Dr Patel:
Yes, and now we have 2-year follow-up data for patients from the APPLY and APPOINT studies.^3,4 They were presented in June of 2025,¹⁷ and I cannot wait to discuss the results!

Dr Chand:
Absolutely, and I think the importance of having long-term data is that you can see if there are any changes to the known safety or efficacy profile of the treatment.

Dr Patel:
Not to mention having this 2-year long-term data can give both patients and us, their health care professionals, greater confidence in using a particular therapy.

Dr Chand:
Long-term data also help us address the goals we have for our patients—not just treating the symptoms of PNH but ensuring that long-term complications such as breakthrough hemolysis and major adverse vascular events are addressed. So, I think it’s important to have the long-term data of a drug to assess that.

Dr Patel:
Before we dive into our discussion and the data, it’s important we first take a moment to review the indication and Important Safety Information for FABHALTA. To see the full Prescribing Information, please visit www.FABHALTA-HCP.com.

Voiceover:

INDICATION
FABHALTA^® (iptacopan) is indicated for the treatment of adults with paroxysmal nocturnal hemoglobinuria (PNH).

IMPORTANT SAFETY INFORMATION

WARNING: SERIOUS INFECTIONS CAUSED BY ENCAPSULATED BACTERIA
FABHALTA, a complement inhibitor, increases the risk of serious infections, especially those caused by encapsulated bacteria, such as Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae type b. Life-threatening and fatal infections with encapsulated bacteria have occurred in patients treated with complement inhibitors. These infections may become rapidly life-threatening or fatal if not recognized and treated early.

• Complete or update vaccinations for encapsulated bacteria at least 2 weeks prior to the first dose of FABHALTA, unless the risks of delaying therapy with FABHALTA outweigh the risk of developing a serious infection. Comply with the most current Advisory Committee on Immunization Practices (ACIP) recommendations for vaccinations against encapsulated bacteria in patients receiving a complement inhibitor.
• Patients receiving FABHALTA are at increased risk for invasive disease caused by encapsulated bacteria, even if they develop antibodies following vaccination. Monitor patients for early signs and symptoms of serious infections and evaluate immediately if infection is suspected.

Because of the risk of serious infections caused by encapsulated bacteria, FABHALTA is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the FABHALTA REMS.

Dr Patel:
So, let’s see what the data tell us. But before delving into the data for FABHALTA and looking at the 2-year rollover extension program, or REP, results for the APPLY and APPOINT studies, it’s important to review the relevant parent studies.

Dr Chand:
Yes, and I think it would be useful to see the APPLY and APPOINT trial designs first.

Dr Patel:
As you’ll recall, the efficacy and safety of FABHALTA was evaluated in 2 multicenter, open-label, phase 3 trials that included a treatment period of 24 weeks.^5,18,19 The APPLY trial was an open-label, active comparator–controlled study that enrolled C5 inhibitor–experienced adult patients with PNH who had hemoglobin less than 10 g/dL despite treatment with a stable regimen of eculizumab or ravulizumab for at least 6 months. The vast majority of our patients with PNH are still treated with C5 inhibition. So, for me, it was and still is a very reasonable active comparator arm.^5,6

The APPLY trial enrolled 97 adult patients who were randomized in an 8:5 ratio either to switch to FABHALTA monotherapy or continue their C5 inhibitor therapy during the 24-week randomized treatment period.⁵ This was followed by a 24-week treatment extension period where patients in the FABHALTA arm were offered to continue on and patients in the C5 inhibitor arm were offered to switch to FABHALTA.⁵

The first primary end point in the APPLY trial was the proportion of patients who achieved sustained hemoglobin increase of greater than or equal to 2 g/dL from their baseline without a need for red blood cell transfusion after 24 weeks of treatment.⁵ The APPLY trial’s other primary end point assessed the proportion of patients who achieved sustained hemoglobin level of greater than or equal to 12 g/dL without a need for red blood cell transfusion after 24 weeks.^5,6

Dr Chand:
The APPOINT trial was a single-arm, open-label uncontrolled study that enrolled adult patients with PNH who had hemoglobin less than 10 g/dL and were naive to complement inhibitor therapy.⁵ The APPOINT trial enrolled 40 patients who received FABHALTA for 24 weeks, followed by the 24-week treatment extension period. Eligible patients were offered to enter a rollover extension program.⁵

The primary end point in the APPOINT trial was the proportion of patients who achieved sustained hemoglobin increase of greater than or equal to 2 g/dL from their baseline without a need for additional red blood cell transfusions after 24 weeks of treatment.⁸ Overall, APPLY and APPOINT were well-designed studies, and I feel like the end points were well chosen.

Dr Patel:
The 2-year REP with APPLY and APPOINT is an ongoing, open-label, single-arm, multicenter, phase 3 study that enrolled patients with PNH who completed phase 2 and 3 trials with iptacopan and included both the APPLY and the APPOINT trials.¹⁰ I think this type of long-term data is important to help give providers confidence in more recent therapies.

Dr. Chand, can you take us through the end points?

Dr Chand:
Sure, the primary end point of the rollover extension program was safety. Additional end points included hematological responses; transfusion avoidance; change from baseline in hemoglobin, FACIT-Fatigue, LDH levels; and occurrences of BTH and major adverse vascular events.¹⁰ These end points are aligned with what I look for as a clinician. So, in the short term, it’s about what the patient is presenting with, whether it’s anemia, fatigue, or a need for transfusions.³ And in the long term, it’s ensuring that I have a better grasp on safety.

Now, let’s listen to additional Important Safety Information.

Voiceover:

IMPORTANT SAFETY INFORMATION (continued)

CONTRAINDICATIONS
Patients with serious hypersensitivity to FABHALTA or any of the excipients.
For initiation in patients with unresolved serious infection caused by encapsulated bacteria, including Streptococcus pneumoniae, Neisseria meningitidis, or Haemophilus influenzae type b.

Dr Chand:
Now that we’ve discussed study designs for these FABHALTA PNH clinical trials, let’s discuss the outcomes for the APPLY and APPOINT studies.

Dr Patel:
Starting with the APPLY study, superior and substantial hemoglobin increases were achieved with FABHALTA vs C5 inhibitors through the 24-week randomized treatment period.⁵ 82.3% of patients on FABHALTA achieved a hemoglobin increase of at least 2 g/dL from baseline in the absence of RBC transfusions compared with 0% of patients on C5 inhibitors.⁵ Hemoglobin levels of 12 g/dL or higher without RBC transfusions after 24 weeks were achieved in 67.7% of patients on FABHALTA compared with 0% of patients on C5 inhibitors.⁵ Normal hemoglobin levels vary but generally are between 12 to 16 g/dL for women and 13 to 18 g/dL for men.^20,21

Thinking about normalization, there is certainly a balance between achieving it and understanding what's possible for your patient's PNH treatment. Treatment goals in PNH with regards to hemoglobin should be tailored to the patient’s needs.

Now, when we look at the APPOINT study, it’s also evident that sustained hemoglobin improvements without the need for RBC transfusions are within reach.⁵ 77.5% of patients on FABHALTA achieved a sustained increase between Day 126 and Day 168 in hemoglobin levels from baseline of at least 2 g/dL in the absence of RBC transfusions, based on central laboratory hemoglobin values. In a sensitivity analysis, 87.5% of patients achieved a sustained increase in hemoglobin levels from baseline of at least 2 g/dL in the absence of RBC transfusions, including local laboratory hemoglobin values when central laboratory values were not available.⁵

Dr Chand:
For APPOINT, it must be noted that the additional end point of sustained hemoglobin levels of 12 g/dL or higher without red blood cell transfusions after 24 weeks is from an additional analysis and is exploratory in nature. It is not subject to family-wise Type 1 error, and no formal conclusions can be made. In APPOINT, a response rate of 47.5% was observed.¹¹

Dr. Patel, I remember the excitement around the APPLY and APPOINT studies a couple of years ago when the complement inhibitor space just exploded with additional therapies and data releases.

Dr Patel:
Absolutely. There was a lot of speculation about what a proximal inhibitor like FABHALTA could mean for patients and how it would perform in clinical trials. That being said, what other efficacy end points were assessed in both the APPLY and APPOINT studies?

Beyond hemoglobin normalization, C5 inhibitor–experienced patients in APPLY treated with FABHALTA experienced an adjusted mean change in hemoglobin level from baseline of plus 3.6 g/dL vs minus 0.1 with C5 inhibitors.⁵

In APPOINT, again, this end point is from an additional analysis and is exploratory in nature. It is not subject to family-wise Type 1 error and no formal conclusions can be made. Nonetheless, we see here that patients taking FABHALTA experienced an adjusted mean hemoglobin change increase of 4.29 g/dL from baseline.¹¹

Dr Chand:
Dr. Patel, I would also like to stress the implications of what hemoglobin increases can mean to a patient, depending on their baseline. So, for example, if a patient goes from a hemoglobin level of 7 to 9 after treatment, this can mean that they might no longer need red blood cell transfusions. I think transfusion avoidance can have big implications for a person with PNH who may no longer require infusion center or ER visits. That’s huge, in my opinion.

Dr Patel:
Valid points, and I agree. Dr. Chand, and now that you’ve mentioned it, what did we see in terms of transfusion avoidance in both studies?

Dr Chand:
Transfusion avoidance can have major implications for patients, so it was great to see that in the APPLY study the transfusion avoidance rate for FABHALTA-treated patients was significantly higher than in C5 inhibitor–treated patients between Week 2 and Week 24.⁵

In the APPOINT study, the data were taken from additional analyses and are exploratory; therefore, no formal conclusions can be made, but the rate of transfusion avoidance between Week 2 and Week 24 was 100%.¹¹

Dr Patel:
When we talk about any treatment, it’s not just about efficacy. We also have to consider safety. Long-term safety is important for a chronic disease like PNH. It’s critical, with any therapy, that you assess the safety not just in the immediate short term but long term as well.

Dr Chand:
Yes, exactly. I think the 24-week data help us understand what risks might be associated with FABHALTA, but long-term follow-up is needed for chronic diseases like PNH, as you mentioned.

So, what do we see in terms of safety? In APPLY, the adverse reactions reported in greater than 5% of adults with PNH treated with FABHALTA vs C5 inhibitors were, respectively: headache in 19% vs 3% of patients; nasopharyngitis in 16% vs 17%; diarrhea in 15% vs 6%; abdominal pain in 15% vs 3%; bacterial infection in 11% vs 11%; nausea in 10% vs 3%; viral infection in 10% vs 31%; arthralgia in 8% vs 3%; thrombocytopenia, dizziness, systemic hypertension, lipid disorder in 6% vs 0%, and rash in 3% vs 0% of patients.⁵

Serious adverse reactions included pyelonephritis, urinary tract infection, and COVID-19.⁵ 43% of FABHALTA-treated patients experienced any grade thrombocytopenia during the randomized treatment period.⁵ Three of those patients experienced decreased platelets that worsened to grade greater than or equal to 3 from baseline.⁵ No patients discontinued FABHALTA or C5 inhibitors due to an adverse reaction during the 24-week randomized treatment period.⁶ One patient discontinued FABHALTA due to pregnancy.⁶

In APPOINT, adverse reactions reported in greater than 5% of patients included headache in 28% of patients, viral infection in 18% of patients, nasopharyngitis in 15% of patients, rash in 10% of patients, abdominal pain in 8% of patients, diarrhea in 8% of patients, and lipid disorder in 8% of patients.⁵

Serious adverse reactions were reported in 2 patients and included COVID-19 and bacterial pneumonia.⁵ Bacterial infection and nausea were each reported in 5% of patients.⁵ Dizziness and urticaria were each reported in 3% of patients.⁵ Additionally, no patient discontinued FABHALTA due to an adverse reaction in the core treatment period of the APPOINT study.⁹

Dr Patel:
Because of the risk of serious infections caused by encapsulated bacteria, FABHALTA is only available through a restricted program under a REMS called FABHALTA REMS.⁵ So, even after my patient and I have determined that FABHALTA is the right choice, I still need to fulfill the requirements of the FABHALTA REMS to start them on their FABHALTA journey.⁵

The next step is to vaccinate my patients at least 2 weeks before starting treatment and updating as required by the ACIP guidelines. Vaccination against encapsulated bacteria, including Neisseria meningitidis and Streptococcus pneumoniae, is required.⁵ If urgent FABHALTA therapy is indicated in a patient who is not up to date with vaccines against encapsulated bacteria, provide the patient with antibacterial drug prophylaxis and administer these vaccines as soon as possible.⁵

The last step is choosing between 2 specialty pharmacies certified under the REMS program to dispense FABHALTA medication.⁵

Dr Chand:
Dr. Patel, I think 2 things many of us HCPs focus on in terms of safety when it comes to our patients are breakthrough hemolysis and major adverse vascular events. Why are breakthrough hemolysis and major adverse vascular events of interest in PNH?

Dr Patel:
Well, breakthrough hemolysis can be a possible indicator that may be telling us a treatment may not be fully controlling the PNH. So, we want to monitor for that. In the case of major adverse vascular events, it is a serious, possibly life-threatening vascular event, so we want to be especially vigilant of that, and one of the key goals of treatment, in my opinion, is prevention. So, what does the APPLY study tell us about the rates of both breakthrough hemolysis and major adverse vascular events in FABHALTA-treated patients?

For APPLY, data on both breakthrough hemolysis and major adverse vascular events are exploratory. It is important to note that no formal conclusions or comparisons between the 2 treatment arms should be made.⁶ During the 24-week randomized treatment period, the annualized rate of clinical breakthrough hemolysis was 0.07 in patients treated with FABHALTA, and 0.67 in patients treated with C5 inhibitors.⁶

Regarding the annualized rate of major adverse vascular events between FABHALTA and C5 inhibitors, there was no statistically significant difference. One patient experienced transient ischemic attack in the FABHALTA arm, which was deemed unrelated to treatment by the investigator.⁶

Dr Chand:
Again, in looking at the data from APPOINT, no formal conclusions should be made. During the 24-week core treatment period, there were no clinical breakthrough hemolysis or major adverse vascular events.⁹ From a safety perspective, I think it’s important to realize that every medication has its own toxicity profile, but the key, in my opinion, is to know what might be an issue, recognize it, and manage it as well as possible if it happens.

Dr Patel:
Absolutely. I think it’s also reassuring when we, as HCPs, see a side effect profile with no surprises compared to what we have previously encountered when treating patients with PNH. Now, having long-term data, I think that further strengthens our confidence in using a drug like FABHALTA and recommending it to appropriate patients.

Let’s hear more Important Safety Information.

Voiceover:

IMPORTANT SAFETY INFORMATION (continued)

WARNINGS AND PRECAUTIONS

Serious Infections Caused by Encapsulated Bacteria

• FABHALTA, a complement inhibitor, increases a patient’s susceptibility to serious, life-threatening, or fatal infections caused by encapsulated bacteria, including Streptococcus pneumoniae, Neisseria meningitidis (caused by any serogroup, including nongroupable strains), and Haemophilus influenzae type b. Life-threatening and fatal infections with encapsulated bacteria have occurred in both vaccinated and unvaccinated patients treated with complement inhibitors. The initiation of FABHALTA is contraindicated in patients with unresolved serious infections caused by encapsulated bacteria.
• Complete or update vaccination against encapsulated bacteria at least 2 weeks prior to the start of FABHALTA, according to the current ACIP recommendations for patients receiving a complement inhibitor. Revaccinate patients in accordance with ACIP recommendations considering the duration of therapy with FABHALTA. Note that ACIP recommends an administration schedule in patients receiving complement inhibitors that differs from the administration schedule in the vaccine prescribing information. If urgent FABHALTA therapy is indicated in a patient who is not up to date with vaccines against encapsulated bacteria according to ACIP recommendations, provide the patient with antibacterial drug prophylaxis and administer these vaccines as soon as possible. The benefits and risks of treatment with FABHALTA, as well as the benefits and risks of antibacterial drug prophylaxis in unvaccinated or vaccinated patients, must be considered against the known risks for serious infections caused by encapsulated bacteria.
• Vaccination does not eliminate the risk of serious encapsulated bacterial infections, despite development of antibodies following vaccination. Closely monitor patients for early signs and symptoms of serious infection and evaluate patients immediately if an infection is suspected. Inform patients of these signs and symptoms and instruct patients to seek immediate medical care if they occur. Promptly treat known infections. Serious infection may become rapidly life-threatening or fatal if not recognized and treated early. Consider interruption of FABHALTA in patients who are undergoing treatment for serious infections, depending on the risks of interrupting treatment in the disease being treated.

Dr Patel:
I think this is the part we've been waiting for! I know, personally, I was eager to see the 2-year rollover extension program results. How about you, Dr Chand?

Dr Chand:
Oh. I think all our peers were excited about this, because, from my experience, people tend to get more comfortable with treatments whenever there are longer-term data.

Dr Patel:
Before we begin, it’s important to note that these data are for observation only and no conclusions should be made from these data. Looking at hemoglobin levels for the APPLY rollover extension program patients at 2 years, we saw 58 out of 84 patients, or 69%, achieved hemoglobin levels of at least 12 g/dL, regardless of their transfusion status.³

In APPOINT rollover extension program patients, we saw the following number and percentages of patients achieve hemoglobin levels of at least 12 g/dL³:

• 30 out of 40 patients, or 75%, within the group who had no RBC transfusions within the prior 12 months achieved this end point.
• Irrespective of RBC transfusions, 31 out of 40 patients, or 77.5%, achieved this end point.

And finally, when combining both groups, we saw the following number and percentages of patients achieve hemoglobin levels of at least 12 g/dL³:

• 88 out of 124 patients, or 71%, within the group who had no RBC transfusions within the prior 12 months achieved this end point.
• 89 out of 124 patients, or 71.8%, within the group, irrespective of RBC transfusions, achieved this end point.

I don’t know about you, Dr Chand, but for me, there is something to be said about seeing hemoglobin normalization out at 2 years of follow-up. I don’t find these data to be super surprising however, and I was kind of expecting and hoping to see numbers like this.

Dr Chand:
I agree. When we think about these responses, these long-term data add more information for us to consider when choosing appropriate patients for FABHALTA. Now, we obviously can’t make any conclusions around these data. This is a long-term extension study that provides additional support when we are engaged in shared decision-making with our patients. But as you said, Dr Patel, the data are reassuring and what we were really hoping to see.

Now looking at a hemoglobin increase of at least 2 g/dL in our APPLY REP patients, we saw the following number and percentages of patients who achieved this end point³:

• 67 out of 84 patients, or 79.8%, within the group who had no RBC transfusions within the prior 12 months achieved this end point.
• Irrespective of RBC transfusions, 69 out of 84 patients, or 82.1%, achieved this end point.

Regarding our APPOINT REP patients, we saw the following number and percentages of patients who achieved a hemoglobin increase of at least 2 g/dL³:

• 34 out of 40 patients, or 85%, within the group who had no RBC transfusions within the prior 12 months achieved this end point.
• Irrespective of RBC transfusions, 35 out of 40 patients, or 87.5%, within the group achieved this end point.

And finally, for APPLY and APPOINT combined rollover extension program patients, we saw the following number and percentages of patients who achieved a hemoglobin increase of at least 2 g/dL³:

• 101 out of 124 patients, or 81.5%, who had no RBC transfusions within the prior 12 months achieved this end point.
• Irrespective of RBC transfusions, 104 out of 124 patients, or 83.9%, achieved this end point.

I personally feel an increase of 2 g/dL is important to my patients because it could be the difference between being transfusion dependent and transfusion independent. What do you think, Dr Patel?

Dr Patel:
I think you said it perfectly. Obviously, this study wasn’t powered for any clinical conclusions, so we always keep that in mind. But when discussing options with your patients, it’s nice to put end points like these in terms they might understand. Ultimately, it’s about helping patients get better control of their PNH. And having 2-year data provides additional support to those discussions with patients.

Dr Patel:
Also included in the rollover extension program was a mean change from baseline in hemoglobin levels and transfusion avoidance.³ For patients in the APPLY rollover extension program, the mean increase from baseline was 3.2 g/dL; for patients in the APPOINT rollover extension program, it was 5.37 g/dL. That equates to a mean of 3.90 g/dL in the combined cohort.³ 90.4% of patients in the combined cohort avoided transfusions during this study period. This was true for 95% of patients in the APPOINT rollover extension program and 88.5% in the APPLY rollover extension program.³

As a reminder, APPLY patients were C5 inhibitor–experienced patients, while APPOINT patients were complement inhibitor–naive, so this may influence the numbers we are seeing here.⁵

In totality, without pointing to one trial or one end point, the data allow providers and patients to feel more empowered when they are having those joint decision-making discussions about selecting a complement inhibitor. I would certainly say that discussion looks different today than it did when FABHALTA was first approved.

Dr Chand:
Yes, and to add some more perspective, we always hear from patients that they want long-term data, especially in PNH, because long-term efficacy and safety are important to them. For example, I had a patient on a C5 inhibitor for years who was never able to achieve hemoglobin normalization. We recently reexamined whether we needed to make a change. So, I agree, it’s really nice to have 2-year data from FABHALTA. I always present patients with all of the options—with the data available for each—and determine which dosing option works best for that patient.

With all the options we have available to us, this is what is exciting to me about PNH right now. We have the power to choose what's most appropriate for our patients because there are more options, like FABHALTA, for us to explore.^5,12-16

Dr Patel:
I echo your sentiments, Dr Chand. Now, let’s wrap up by talking about safety for this 2-year REP with APPLY and APPOINT datasets.

Dr Chand:
Here we see the frequency of events along with exposure in patient-years. For the 2-year rollover extension program safety for treatment-emergent adverse events through 2 years, a frequency threshold of 10% or higher was selected. This is to account for the expected increase in frequency of treatment-emergent adverse events that is due to the longer observation period. As a reminder, this is 2 years of exposure to FABHALTA in the rollover extension program vs 24 weeks exposure in APPLY and APPOINT.⁴

For APPLY rollover extension program, the 5 most frequent adverse events included COVID-19 in 49% of patients, headache in 16.7% of patients, diarrhea in 18.8% of patients, nasopharyngitis in 22.9% of patients, and nausea in 14.6% of patients.⁴

For a total exposure of 183.6 patient-years, the 6 most frequent adverse events were 53 events of COVID-19, 35 events of headache, 26 events of diarrhea, 32 events of nasopharyngitis, 19 events of nausea, and 19 events of breakthrough hemolysis.⁴

For APPOINT rollover extension program, the 5 most frequent adverse events included COVID-19 in 40% of patients, headache in 32.5% of patients, diarrhea in 20% of patients, upper respiratory tract infection in 35% of patients, and abdominal pain in 15% of patients.⁴

For a total exposure of 80 patient-years, the 6 most frequent adverse events were 19 events of COVID-19, 16 events of headache, 9 events of diarrhea, 18 events of upper respiratory tract infection, 6 events of abdominal pain, and 6 events of pyrexia.⁴

For the combined APPLY and APPOINT cohort of patients, the 5 most frequent adverse events were COVID-19 in 46.3% of patients, headache in 21.3% of patients, diarrhea in 19.1% of patients, upper respiratory tract infection in 17.6% of patients, and nasopharyngitis in 16.9% of patients.⁴

For a total exposure of 263.6 patient-years, the 5 most frequent adverse events were 72 events of COVID-19, 51 events of headache, 35 events of diarrhea, 36 events of upper respiratory tract infection, and 33 events of nasopharyngitis.⁴

With any medication, safety is paramount. So, as providers, it’s important that we are aware of the safety profile of a medication so that we can educate our patients and be prepared to address anything they might report.

Dr Patel:
Breakthrough hemolysis is something all clinicians, I believe, tend to look closely at, so let’s review the results from the 2-year rollover extension program. Again, these data are for observational purposes only and no formal conclusions can be made.¹⁰ In APPLY rollover extension program patients, there were 11.5% who experienced a breakthrough hemolysis event, which is 19 events per 100 patient-years.³

In APPOINT rollover extension program patients, there were 7.5% of patients that experienced a breakthrough hemolysis event, which is 3 events per 100 patient-years.³ In the total patient cohort, 10.3% of patients experienced a breakthrough hemolysis event, which is 22 events per 100 patient-years.³

Dr Chand:
Finally, regarding major adverse vascular events, in APPLY rollover extension program patients, there were 3.1% of patients that experienced at least 1 major adverse vascular event, which is 4 events per 100 patient-years.³ In APPOINTrollover extension program patients, there were 0 events of major adverse vascular events.³ In the combined APPLY and APPOINT cohort of patients, there were 2.2% of patients that experienced a major adverse vascular event, which is 4 events per 100 patient-years.³

Dr Patel:
Thank you, Dr Chand, for sharing your insights. We went through a lot of information and perspectives today. Personally, I think the full data package from the APPLY and APPOINT studies builds my confidence in knowing when to use FABHALTA in appropriate patients.

These results continue to add to the evidence of FABHALTA use for our patients who are interested in an oral monotherapy option that also offers the potential for normal hemoglobin levels and effective disease control. Of course, as with any treatment, we base our clinical decisions on the pivotal data, in this case APPLY and APPOINT, but when having joint decision-making discussions with patients, it's nice to keep these long-term data in the back of your mind.^5,8

Dr Chand:
It was a joy to get your thoughts, Dr Patel, and I couldn’t agree more. I feel knowledge is important, and it’s never a bad thing to have more information to help guide our treatment discussions. I totally agree the pivotal data are where we start, but knowing we have more information about FABHALTA can help us make better informed and shared decisions with our patients about what best suits their needs and their preferences.

Every patient is different. Some are young active patients. Others may be caregivers for family members, while some others may have full-time jobs. In these cases, going to an infusion center may take time out of their already busy schedules. So, I do believe our treatment decisions can have an impact on the day-to-day of patients.

Dr Patel:
It’s a really exciting time to be able to treat PNH. At the end of the day, we are empowering our patients to become more independent and not be defined by their disease. So, you can aim to pick the most appropriate therapy for your patient but also help your patient pick that therapy with you. So, it's a joint decision. And for anyone watching this video, I encourage you to scan the QR code at the end of the video and explore all the data for FABHALTA!

Continue watching for the full Important Safety Information, including the Boxed WARNING and Medication Guide.

To see the full Prescribing Information, please visit www.FABHALTA-HCP.com .

Dr Chand:
I love that, and I think that’s a beautiful note to end on.

Voiceover:

CONTRAINDICATIONS

• Patients with serious hypersensitivity to FABHALTA or any of the excipients.
• For initiation in patients with unresolved serious infection caused by encapsulated bacteria, including Streptococcus pneumoniae, Neisseria meningitidis, or Haemophilus influenzae type b.

WARNINGS AND PRECAUTIONS

Serious Infections Caused by Encapsulated Bacteria

• FABHALTA, a complement inhibitor, increases a patient’s susceptibility to serious, life-threatening, or fatal infections caused by encapsulated bacteria, including Streptococcus pneumoniae, Neisseria meningitidis (caused by any serogroup, including nongroupable strains), and Haemophilus influenzae type b. Life-threatening and fatal infections with encapsulated bacteria have occurred in both vaccinated and unvaccinated patients treated with complement inhibitors. The initiation of FABHALTA is contraindicated in patients with unresolved serious infections caused by encapsulated bacteria.
• Complete or update vaccination against encapsulated bacteria at least 2 weeks prior to the start of FABHALTA, according to the current ACIP recommendations for patients receiving a complement inhibitor. Revaccinate patients in accordance with ACIP recommendations considering the duration of therapy with FABHALTA. Note that ACIP recommends an administration schedule in patients receiving complement inhibitors that differs from the administration schedule in the vaccine prescribing information. If urgent FABHALTA therapy is indicated in a patient who is not up to date with vaccines against encapsulated bacteria according to ACIP recommendations, provide the patient with antibacterial drug prophylaxis and administer these vaccines as soon as possible. The benefits and risks of treatment with FABHALTA, as well as the benefits and risks of antibacterial drug prophylaxis in unvaccinated or vaccinated patients, must be considered against the known risks for serious infections caused by encapsulated bacteria.
• Vaccination does not eliminate the risk of serious encapsulated bacterial infections, despite development of antibodies following vaccination. Closely monitor patients for early signs and symptoms of serious infection and evaluate patients immediately if an infection is suspected. Inform patients of these signs and symptoms and instruct patients to seek immediate medical care if they occur. Promptly treat known infections. Serious infection may become rapidly life-threatening or fatal if not recognized and treated early. Consider interruption of FABHALTA in patients who are undergoing treatment for serious infections, depending on the risks of interrupting treatment in the disease being treated.

FABHALTA REMS

• FABHALTA is available only through a restricted program under a REMS called FABHALTA REMS, because of the risk of serious infections caused by encapsulated bacteria.
• Under the FABHALTA REMS, prescribers must enroll in the program. Prescribers must counsel patients about the risks, signs, and symptoms of serious infections caused by encapsulated bacteria, provide patients with the REMS educational materials, ensure patients are vaccinated against encapsulated bacteria, prescribe antibacterial drug prophylaxis if patients’ vaccine status is not up to date and treatment must be started urgently, and provide instructions to always carry the Patient Safety Card during treatment and for 2 weeks following last dose of FABHALTA.
• Further information is available by telephone: 1-833-993-2242 or online at www.FABHALTA-REMS.com.

Monitoring of PNH Manifestations After FABHALTA Discontinuation

• After discontinuing FABHALTA, closely monitor patients for at least 2 weeks after the last dose for signs and symptoms of hemolysis. These signs include elevated lactate dehydrogenase (LDH) levels along with sudden decrease in hemoglobin or PNH clone size, fatigue, hemoglobinuria, abdominal pain, dyspnea, major adverse vascular events (such as thrombosis, stroke, and myocardial infarction), dysphagia, or erectile dysfunction. If discontinuation of FABHALTA is necessary, consider alternative therapy.
• If hemolysis occurs after discontinuation of FABHALTA, consider restarting treatment with FABHALTA, if appropriate, or initiating another treatment for PNH.

Hyperlipidemia

• FABHALTA may increase total cholesterol, LDL cholesterol, and serum triglycerides.
• Of 88 FABHALTA-treated patients who had normal total cholesterol at baseline, 31 developed grade 1 hypercholesterolemia during the randomization or core treatment period and 1 patient worsened from baseline grade 1 to grade 2.
• Of 96 FABHALTA-treated patients with LDL cholesterol ≤ 130 mg/dL at baseline during the randomization or core treatment period, 14 patients developed LDL cholesterol > 130-160 mg/dL, 6 patients developed LDL cholesterol > 160-190 mg/dL and 4 patients developed LDL cholesterol > 190 mg/dL.
• Of 89 FABHALTA-treated patients with normal triglycerides during the randomization or core treatment period, 22 patients developed grade 1 elevated triglycerides. Three patients experienced an increase in triglycerides from grade 1 to grade 2.
• Of the 102 FABHALTA-treated patients in APPLY-PNH and APPOINTPNH, 2 patients required cholesterol-lowering medications.
• Monitor serum lipid parameters periodically during treatment with FABHALTA and initiate cholesterol-lowering medications, if indicated.

ADVERSE REACTIONS

• The most common adverse reactions (≥10%) in adults with PNH receiving FABHALTA were headache, nasopharyngitis, diarrhea, abdominal pain, bacterial infection, viral infection, nausea, and rash.

DRUG INTERACTIONS

• Concomitant use of CYP2C8 inducers (eg, rifampin) may decrease iptacopan exposure, which may result in loss of or reduced efficacy of FABHALTA. Monitor the clinical response and discontinue use of the CYP2C8 inducer if loss of efficacy of FABHALTA is evident.
• Concomitant use of strong CYP2C8 inhibitors (eg, gemfibrozil) may increase iptacopan exposure, which may result in increased risk for adverse reactions with FABHALTA. Coadministration with a strong CYP2C8 inhibitor is not recommended.

USE IN SPECIFIC POPULATIONS

• Because of the potential for serious adverse reactions in a breastfed child, breastfeeding should be discontinued during treatment and for 5 days after the final dose.
• FABHALTA is not recommended in patients with severe hepatic impairment (Child-Pugh class C). No dose adjustment is required for patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment. 

Please see full Prescribing Information, including Boxed WARNING and Medication Guide.

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