Personalizing PNH Care: Exploring the Role of Iptacopan in Clinical Practice

Announcer:
Welcome to ReachMD. This medical industry feature, “Flipping the Switch,” is sponsored by Novartis Pharmaceuticals Corporation. This program is intended for health care professionals. Here’s your host, Steve Stone, a hematology specialist from Bronson Healthcare in Kalamazoo, Michigan.

Steve Stone:
Picture this: another busy day in clinic where every patient with PNH tells a different story. While they share the same diagnosis, you see a range of hemoglobin levels and symptoms.^1,2 You know what works for one patient might not work for another, so how do you navigate the complexities of PNH management? It makes knowing when to appropriately switch treatments in patients with PNH quite challenging. Having been in a similar situation, I reached out to Dr Srinivasa Sanikommu at Atrium Health Levine Cancer Institute in Charlotte, North Carolina, who has been treating patients with PNH for more than 20 years.

I’m your host, Steve Stone, and I’m happy to bring you our podcast, “Flipping the Switch”.

This podcast is sponsored by Novartis Pharmaceuticals Corporation, and the speakers have been compensated for their time.

In this episode, we’ll discuss switching patients with hemoglobin <10 g/dL from eculizumab or ravulizumab to FABHALTA^® (iptacopan) supported by the APPLY study, tailoring treatment goals for patients with PNH, and the unmet needs in those with hemoglobin ≥10 g/dL on eculizumab or ravulizumab. More to come when we return after a review of some Important Safety Information for FABHALTA.

Announcer:

INDICATION
FABHALTA 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.

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.

Steve Stone:
And we’re back with our guest! Dr Sanikommu, great to have you!

Dr Sanikommu:
Of course, Steve.

Steve Stone:
Dr Sanikommu, what is your experience with managing patients who have switched to FABHALTA from eculizumab or ravulizumab?

Dr Sanikommu:
I’ll never forget my first patient who switched to FABHALTA. Her hemoglobin level jumped from around 8 g/dL to 13 g/dL in just a month! Before switching, she hadn’t realized she had accepted her current state as her new “normal”.

I’ve seen similar results switching other adult patients with PNH to FABHALTA. These patients have experienced extravascular hemolysis, or EVH, and ongoing challenges like residual anemia and transfusion dependence.^3,4 Personally, I believe I can try to do more for them.

Steve Stone:
Residual anemia is a persistent issue in some of my patients with PNH as well, prompting me to consider switching treatments. I believe that although C5 inhibitors have reduced mortality and morbidity in patients with PNH, FABHALTA may offer them another treatment option that can match their individual needs and goals.⁵

Dr Sanikommu:
FABHALTA has shown potential in my patients. Not only does FABHALTA offer comprehensive hemolysis control of EVH and intravascular hemolysis, or IVH, but its oral monotherapy dosing means they no longer have to schedule complement inhibitor infusion appointments.⁶ To me, that’s a win-win.

Steve Stone:
Dr Sanikommu, your experience with FABHALTA makes me think of the phase 3 APPLY study.^6,7

Dr Sanikommu:
That’s true. APPLY was a phase 3, randomized, open-label, active comparator–controlled trial to assess the efficacy and safety of switching to FABHALTA compared with continuing on IV C5i therapy for a core treatment period of 24 weeks.^6,8

This international study included both US-approved and non–US-approved eculizumab or ravulizumab.^6,8 All 97 patients who were included in the study had residual anemia, defined as a mean hemoglobin <10 g/dL, despite previous treatment with a stable regimen of C5i for at least 6 months.^7,8

The patients were randomized in an 8:5 ratio, where 62 patients were switched to FABHALTA 200 mg orally twice daily and 35 patients continued on their C5i regimen, which included 23 patients on eculizumab and 12 patients on ravulizumab.^7,8

Steve Stone:
The two primary end points of APPLY included the proportion of patients achieving sustained hemoglobin increases of ≥2 g/dL from baseline without a need for RBC transfusions, and the proportion of patients achieving a sustained hemoglobin level of ≥12 g/dL without a need for RBC transfusions.⁸

Dr Sanikommu:
For the first co-primary end point, significantly more patients achieved hemoglobin improvements in the absence of RBC transfusions with FABHALTA vs C5is after the 24-week randomized treatment period.^6,8

The response rate for increasing hemoglobin levels at least 2 g/dL from baseline and in the absence of RBC transfusions was 82.3% in patients who switched to FABHALTA. For patients who continued on their C5i therapy, the response rate was 0%.⁶

For the second co-primary end point, the response rate for hemoglobin levels ≥12 g/dL in the absence of RBC transfusions was 67.7% for those who switched to FABHALTA vs 0% for patients who continued on C5is.⁶ I typically refer to this as “hemoglobin normalization” because, although normal hemoglobin levels may vary, they’re generally between 12-16 g/dL for women and 13-18 g/dL for men.^9,10

Steve Stone:
Did those findings reflect what you’ve seen in your own practice?

Dr Sanikommu:
Yes, and it strengthens my confidence in considering the switch to FABHALTA, when appropriate.

Steve Stone:
That’s reassuring to hear. While efficacy is important, the safety profile of a PNH therapy is equally, if not more, critical.

In terms of safety, during the 24-week randomized treatment period, the adverse reactions reported in >5% of adults with PNH treated with FABHALTA vs C5is were, respectively: headache in 19% vs 3% of patients, nasopharyngitis in 16% vs 17% of patients, diarrhea in 15% vs 6% of patients, abdominal pain in 15% vs 3% of patients, bacterial infection in 11% vs 11% of patients, nausea in 10% vs 3% of patients, viral infection in 10% vs 31% of patients, arthralgia in 8% vs 3% of patients, and thrombocytopenia, dizziness, systemic hypertension, and lipid disorder in 6% vs 0% of patients.⁶ Serious adverse reactions were reported in 2 adults, or 3% of patients, on FABHALTA and included pyelonephritis, urinary tract infection, and COVID-19.⁶ Rash was reported in 2 patients (3%).⁶ Of the 37 FABHALTA-treated patients who had normal platelet counts at baseline, 43% experienced any grade thrombocytopenia during the randomized treatment period.⁶ Three FABHALTA-treated patients experienced decreased platelets that worsened to grade ≥3 from baseline. This included one patient with normal platelets that worsened to grade 4, one patient with baseline grade 1 that worsened to grade 4, and one patient with baseline grade 3 that worsened to grade 4.⁶

No patients discontinued FABHALTA or C5is due to an adverse reaction during the 24-week randomized treatment period.⁶

Dr Sanikommu:
The safety seen in the randomized treatment period is important, and this, combined with its efficacy, is why FABHALTA has allowed me to stay open-minded when managing adult patients with PNH. 

As part of that approach, an important consideration for FABHALTA is the risk of infection. Because of the risk of serious infections caused by encapsulated bacteria, FABHALTA is only available through a Risk Evaluation and Mitigation Strategy, or REMS, program that requires vaccinations before starting FABHALTA.⁶ For more information, please visit https://www.fabhalta-rems.com.

Steve Stone:
It's also important to be aware of Warnings and Precautions for FABHALTA, detailed in the Important Safety Information. Let's hear more about the risk of serious infections caused by encapsulated bacteria.

Announcer:
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.

Steve Stone:
And we’re back!

As we've learned more about PNH and developed additional treatment options like FABHALTA, the PNH landscape has changed considerably. This evolution has allowed us to focus on other treatment goals. For instance, I believe raising hemoglobin to normal levels can be beneficial in my patients with PNH. And like in myelodysplastic syndrome, or MDS, a goal is to achieve transfusion independence or minimize the need for transfusions, so I think that same mindset really makes sense for managing PNH, too.^11,12

Dr Sanikommu:
That’s an interesting point. I also believe no 2 patients with PNH are alike, so understanding each patient beyond their lab values is critical. That way, I can tailor their treatment plan to best fit their individual needs and preferences.

Steve Stone:
Yes, that emphasis on the individual is key, which is why I think this shift also highlights how important it is to listen to our patients when choosing the appropriate treatment approach for them. One of my patients accepted her ongoing symptoms as her new “normal.” But as her HCP, I wanted her to better understand her condition and feel empowered in managing her care. I remember telling her, “You’re doing much better than before treatment. But it’s important we continue to monitor and assess your PNH symptoms." 

With that in mind, I always encourage open-ended discussions about her symptoms, ensuring she feels heard and actively involved in her treatment plan.

Dr Sanikommu:
That’s a great example. My patients are often vocal about their needs, so I make it a priority to listen closely both to their experiences and to what their symptoms may indicate about their current disease activity. But I also keep in mind that when I see hemoglobin levels that are below the norm or the continued impact of PNH on a patient’s daily life, I know it’s time to speak to the patient about their current treatment and options moving forward.^9,13,14

Overall, I believe we should discuss all PNH treatment options with our patients and support them through shared decision-making, while ultimately guiding them toward the most appropriate treatment choice for their needs.

Steve Stone:
So, we’ve talked a lot of those adults with PNH who have hemoglobin levels below 10 g/dL, but I’m aware that there’s limited data available on those with hemoglobin ≥10 g/dL taking eculizumab or ravulizumab.

Dr Sanikommu, what are your thoughts on this?

Dr Sanikommu:
In my practice, I’ve seen some patients experience ongoing hemolysis despite being on C5is. I fully agree with your observation, and this has made it challenging to assess this patient group. However, I did come across an international study showing that adults with PNH and a hemoglobin level of ≥10 g/dL can still experience signs and symptoms of PNH associated with anemia.¹⁵ However, no definitive conclusions should be made based on these data. 

This was a multinational, web-based, cross-sectional survey of 71 adults with PNH living in France, Germany, and the United Kingdom were assessed for PNH burden; 49 of these patients were treated with eculizumab and 22 were treated with ravulizumab.¹⁵ Patients who were aged ≥18 years and had a self-reported PNH diagnosis were included in the survey.¹⁵ Among 63 patients with self-reported hemoglobin levels, over 85% had hemoglobin levels ≤12 g/dL, with 43% of patients having hemoglobin levels ≥10.5 g/dL.¹⁵ In patients with hemoglobin levels ≥10.5 g/dL, over 66% of patients reported fatigue as the most common symptom, followed by shortness of breath and abdominal pain.¹⁵

The study has several limitations, including reliance on self-reported data prone to bias and recall errors, small sample size, and results that may not be generalizable due to convenience sampling. Some questions may have been interpreted differently by participants, and findings were not adjusted for varying patient characteristics. Real-world data for ravulizumab were only collected in Germany. Additionally, certain measures used, such as the European Organisation for Research and Treatment of Cancer Core Quality of Life questionnaire, or EORTC QLC-C30, and Work Productivity and Activity Impairment, or WPAI, questionnaire, are not validated for use in patients with PNH.¹⁵

That’s a great segue into why I think another study on FABHALTA, called the APPULSE study, is so important for the PNH community. It can provide insights into patients who have switched to FABHALTA from a stable C5 inhibitor regimen of either eculizumab or ravulizumab for at least 6 months.¹⁶

Steve Stone:
Exactly. APPULSE was a 24-week, single-arm, open-label, multicenter, phase 3b study that evaluated the efficacy and safety of switching to FABHALTA 200 mg twice daily in adults with PNH who had achieved hemoglobin levels of 10 g/dL or more in response to a stable regimen of either anti-C5 antibody treatment eculizumab or ravulizumab for at least 6 months and had remained transfusion-free during that period.¹⁶ 52 patients were enrolled following an 8-week screening to confirm eligibility, including transfusion history and vaccination status.¹⁶ All received oral FABHALTA 200 mg twice daily for 24 weeks.¹⁶

Dr Sanikommu:
I also think it’s reassuring that FABHALTA has now been studied across 3 different patient populations.6,16 Besides the APPLY and APPULSE studies, APPOINT was a phase 3, single-arm, open-label, uncontrolled study in complement inhibitor–naive adults with PNH.^6,17 In fact, the approval of FABHALTA as the first oral monotherapy for adults with PNH was based on APPLY and supported by the APPOINT study.¹⁷ Overall, these 3 studies are expanding our perspective on how FABHALTA may fit within the evolving PNH treatment landscape.^6,16

Steve Stone:
You make a great point. Dr Sanikommu, how do you think others may react to having data in 3 patient populations available?

Dr Sanikommu:
Like you and I, I think many of our colleagues will appreciate having this data to support and facilitate collaborative treatment discussions with their patients. At the same time, I would remind them that while multiple treatment options exist, switching should be driven by the patient’s feedback and/or clear clinical needs, like inadequate response to the current therapy, not simply because another option is available.^5,18-20

Steve Stone:
Just so we’re all aware, the most common adverse reactions that were reported in ≥10% of adults with PNH receiving FABHALTA were headache, nasopharyngitis, diarrhea, abdominal pain, bacterial infection, viral infection, nausea, and rash.⁶

Steve Stone:
Any final thoughts for our listeners?

Dr Sanikommu:
One final thing I’d say is, we don’t need to settle. We shouldn’t hesitate to modify our approach, especially now that we have more data to help us make informed choices for different types of patients with PNH.

Steve Stone:
Absolutely. If you’d like to explore the APPULSE study results, check out the 'Peer Perspectives in Practice' video where medical experts in PNH provide their perspectives on FABHALTA data, then take a deeper dive into the data at https://www.fabhalta-hcp.com/pnh/medical-expert-perspectives.

Dr Sanikommu, thank you for taking the time to share your experience! It’s been incredibly valuable!

Dr Sanikommu:
Happy to contribute, Steve!

Steve Stone:
As we close this episode on “Flipping the Switch,” please keep listening to hear the full Important Safety Information for FABHALTA, including the indication and Boxed WARNING. More details are available in the full Prescribing Information, including the Boxed WARNING and Medication Guide, via the link on this site or at www.fabhalta-hcp.com/pnh.

Announcer:
INDICATION
FABHALTA 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.

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 APPOINT-PNH, 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. More information is available at www.fabhalta-hcp.com.

Announcer:
This program was sponsored by Novartis Pharmaceuticals Corporation. If you missed any part of this discussion, visit https://reachmd.com/industry-feature. This is ReachMD. Be part of the knowledge.

References:

1. Dingli D, Matos JE, Lehrhaupt K, et al. The burden of illness in patients with paroxysmal nocturnal hemoglobinuria receiving treatment with the C5-inhibitors eculizumab or ravulizumab: results from a US patient survey. Ann Hematol. 2022;101(2):251-263. doi:10.1007/s00277-021-04715-5
2. Schrezenmeier H, Röth A, Araten DJ, et al. Baseline clinical characteristics and disease burden in patients with paroxysmal nocturnal hemoglobinuria (PNH): updated analysis from the International PNH Registry. Ann Hematol. 2020;99(7):1505-1514. doi:10.1007/s00277-020-04052-z
3. Brodsky RA. Paroxysmal nocturnal hemoglobinuria. Blood. 2014;124(18):2804-2811. doi:10.1182/blood-2014-02-522128
4. Shammo J, Gajra A, Patel Y, et al. Low rate of clinically evident extravascular hemolysis in patients with paroxysmal nocturnal hemoglobinuria treated with a complement C5 inhibitor: results from a large, multicenter, US real-world study. J Blood Med. 2022;13:425-437. doi:10.2147/JBM.S361863
5. Bektas M, Copley-Merriman C, Khan S, Sarda SP, Shammo JM. Paroxysmal nocturnal hemoglobinuria: current treatments and unmet needs. J Manag Care Spec Pharm. 2020;26(12-b Suppl):S14-S20. doi:10.18553/jmcp.2020.26.12-b.s14
6. Fabhalta. Prescribing information. Novartis Pharmaceuticals Corp.
7. Data on file. Study CLNP023C12302 CSR. Novartis Pharmaceuticals Corp; 2022.
8. Peffault de Latour R, Röth A, Kulasekararaj AG, et al. Oral iptacopan monotherapy in paroxysmal nocturnal hemoglobinuria. N Engl J Med. 2024;390(11):994-1008. doi:10.1056/NEJMoa2308695
9. Cappellini MD, Motta l. Anemia in clinical practice—definition and classification: does hemoglobin change with aging? Semin Hematol. 2015;52(4):261-269. doi:10.1053/j.seminhematol.2015.07.006
10. Billett HH. Hemoglobin and hematocrit. In: Walker HK, Hall WD, Hurst JW, eds. Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd ed. Butterworth Publishers; 1990:718-719.
11. Germing U, Oliva EN, Hiwase D, Almeida A. Treatment of anemia in transfusion-dependent and non-transfusion-dependent lower-risk MDS: current and emerging strategies. Hemasphere. 2019;3(6):e314. doi:10.1097/HS9.0000000000000314
12. Balducci L. Transfusion independence in patients with myelodysplastic syndromes: impact on outcomes and quality of life. Cancer. 2006;106(10):2087-2094. doi:10.1002/cncr.21860
13. Patriquin CJ, Kiss T, Caplan S, et al. How we treat paroxysmal nocturnal hemoglobinuria: A consensus statement of the Canadian PNH Network and review of the national registry. Eur J Haematol. 2019;102(1):36-52. doi:10.1111/ejh.13176
14. Cançado RD, Araújo ADS, Sandes AF, et al. Consensus statement for diagnosis and treatment of paroxysmal nocturnal haemoglobinuria. Hematol Transfus Cell Ther. 2021;43(3):341-348. doi:10.1016/j.htct.2020.06.006
15. Panse J, Sicre de Fontbrune F, Burmester P, et al. The burden of illness of patients with paroxysmal nocturnal haemoglobinuria receiving C5 inhibitors in France, Germany and the United Kingdom: patient-reported insights on symptoms and quality of life. Eur J Haematol. 2022;109(4):351-363. doi:10.1111/ejh.13816
16. Data on file. Study CLNP023C12303 CSR. Novartis Pharmaceuticals Corp; 2024.
17. Novartis receives FDA approval for FABHALTA^® (iptacopan), offering superior hemoglobin improvement in the absence of transfusions as the first oral monotherapy for adults with PNH. Novartis. December 6, 2023. Accessed June 30, 2025. www.novartis.com/news/media-releases/novartis-receives-fda-approval-fabhalta-iptacopan-offering-superior-hemoglobin-improvement-absence-transfusions-first-oral-monotherapy-adults-pnh
18. Shi JJ, Ozcan YM, Santos CIA, Patel H, Shammo J, Bat T. Current landscape of paroxysmal nocturnal hemoglobinuria in the era of complement inhibitors and regulators. Ther Adv Hematol. 2024;15:20406207241307500. doi:10.1177/20406207241307500
19. Oliver M, Patriquin CJ. Paroxysmal nocturnal hemoglobinuria: current management, unmet needs, and recommendations. J Blood Med. 2023;14:613-628. doi:10.2147/JBM.S431493
20. Budych K, Helms TM, Schultz C. How do patients with rare diseases experience the medical encounter? Exploring role behavior and its impact on patient-physician interaction. Health Policy. 2012;105(2-3):154-164. doi:10.1016/j.healthpol.2012.02.018

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