Rewiring Your Thinking in Paroxysmal Nocturnal Hemoglobinuria

Announcer:
Welcome to ReachMD. This medical industry feature, “Rewired Thinking,” 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: 
Imagine that it’s 2020. In your exam room is a new patient, a 32-year-old female who reports fatigue impacting her daily life and experiencing dark urine.

You order some tests. You get the results, and you noticed that the level of fatigue was disproportionate to what might be expected based on a hemoglobin level of 8.5 g/dL. You also find evidence of hemolysis, and the direct Coombs test is negative. You determine it is paroxysmal nocturnal hemoglobinuria, or PNH, but what if that same patient walked into your office today? Based on what we now know and which treatment options have become available, how would your approach be different?

I’m your host, Steve Stone, and I’m happy to bring you this podcast titled “Rewired Thinking.” In today’s episode, we’ll explore the shifting landscape of managing PNH and what it means for our adult patients with PNH and health care professionals, or HCPs.

I reached out to Dr George Yaghmour, a hematologist at Keck Medicine at the University of Southern California (USC) in Los Angeles, CA, to hear his thoughts. Dr Yaghmour has been treating adult patients with PNH for the last 10 years.

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

Thank you so much, Dr Yaghmour, for meeting with me today!  

Dr Yaghmour:
Thanks, Steve. I am happy to be here.  

Steve Stone:
So, I’d love to hear your thoughts on how you make the most appropriate choice for adult patients with PNH and how that is different today vs in 2020.

Dr Yaghmour:
For me, the fundamentals of treating PNH are the same. I conduct a risk/benefit assessment, which involves my patient’s personal or family medical history, comorbidities, and treatment needs. I also take a comprehensive patient history, including their occupation and lifestyle, which can make a difference when considering treatment options. But, Steve, as you mentioned, today, we have more options to consider,^1-7 so naturally, the decision-making process goes beyond the risk/benefit discussion, and we can pay more attention to specific patient needs.

In 2020, if we wanted to use a complement inhibitor in PNH, our 2 options were C5 inhibitors (C5is).^1-3 They work in the same way, but they’re dosed differently.^2,3 Don’t get me wrong. As the first approved complement inhibitors in PNH, C5is were, and still are, revolutionary for how we treat these patients. It was the first time we could provide patients with meaningful disease control. But some patients needed more,^1,8 and today, we are in a better position to treat this disease because of the options available.

Steve Stone:
I would agree wholeheartedly. When C5is were approved for PNH, it marked a shift, a moment where we, as hematologists, could do something differently to manage PNH.^1-3,9

Dr Yaghmour, you mentioned, however, that even when C5is were prescribed, some patients still needed more.¹ Can you expand on that?  

Dr Yaghmour:
Sure. What I meant is that how we prioritized what was right for each patient wasn’t something we could do effectively with only those 2 options.^2,3,9,10

Beyond C5is, alternative complement inhibition treatments available now offer diverse administration or dosing options.^4-7 Some people don’t like intravenous, or IV, infusions or needles and prefer to take pills as their treatment. As I mentioned earlier, patient lifestyle and their occupations are important because these factors may determine how well they can coordinate their schedules around visits for IV infusions.

Having conversations with patients is important so that they understand disease etiology, risks of complications, how hemolysis control in PNH will affect them, and which different options are available to them (whether it’s C5is, Factor B inhibitors, or others). I like to ask my patients: Knowing that you have this disease that will require lifelong treatment, what are your concerns? This helps me understand what option might fit best.

Steve Stone:
Dr Yaghmour, you bring up great points. I also believe we can choose the appropriate treatment for our patients, knowing not all respond equally or present with the same manifestations of PNH.

Dr Yaghmour: 
Absolutely. Related to that, other options can enable us to inhibit different points in the complement pathway, which can have different results in the control of hemolysis and resulting disease manifestation.^4-7

C5is work on the terminal complement pathway and inhibit intravascular hemolysis, or IVH, a driving force of PNH. However, extravascular hemolysis, or EVH, can be a clinical concern in some C5i-treated patients.^8,11 As a result, I find that these patients can still exhibit ongoing symptoms of anemia due to hemolysis requiring red blood cell transfusions.¹¹ 

Steve Stone:
That’s very true. I’ve seen some patients like that in my own clinical practice. After listening to the FABHALTA indication, Boxed WARNING, and contraindications, we’ll explore how this has required a “rewiring” of our conventional thinking and approach to treating PNH, plus where FABHALTA fits into all of this.

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:
Dr Yaghmour can you elaborate on how far we’ve come regarding treatment options in PNH and your thoughts on FABHALTA for your adult patients with PNH?

Dr Yaghmour:
I’ve expanded my thinking to take a more comprehensive view. Now, I’m having ongoing, deeper dialogues with my adult patients to better understand how they are doing with their disease. My goals with each patient differ. Before, it was about controlling hemolysis to prevent thrombosis. And of course, this is still a critical concern in PNH, but now I’m thinking about other meaningful end points. It’s like taking the scenic route. It gets you to your destination, but you get to experience more along the way,

You can now tell your patients there is an oral monotherapy option,^5,10 which is an asset in our treatment toolkit. I tell them I believe the FABHALTA data are comprehensive, I understand the risks and know what to look for and do, and that their experience on it could be a positive one. There are no guarantees, but it’s a possibility for some patients.

Today, patients ultimately own the choice, but HCPs can make this decision with them on a more personal level. As their hematologist, I give my patients the knowledge they need, answer their questions, and share my recommendations. But ultimately, I have my patients choose.

Another consideration for deciding treatment options for my patients is, I think, paying closer attention to patient compliance, especially when considering oral options. Some patients may have compliance issues, but others may be better at taking oral medication. This is something we, as hematologists, have to recognize and manage appropriately now.

Steve Stone: 
Agreed. I can remember when I heard FABHALTA was approved.

Dr Yaghmour:
So can I. Some hematologists had been watching FABHALTA throughout its clinical development. So, when hematologists received the news of the FDA approval based on the APPLY and APPOINT studies, I can say, at least for myself, I was excited. I have patients walk into my office ready to switch since this option has been made available, even without me telling them about FABHALTA. I never saw that in my management of PNH before so it’s very interesting and noteworthy.  

Steve Stone:
I definitely agree with you. FABHALTA is an exciting option to present to patients. FABHALTA offers a way to inhibit a different part of the complement cascade, Factor B, and the opportunity to address both EVH and IVH, with the flexibility of an oral administration. Based on the indication, FABHALTA is an option we can use in either complement inhibitor–naive or C5i-experienced patients.⁵ But, like with any therapy option, I believe HCPs can be challenged with identifying patients who we feel are most appropriate for FABHALTA.

Help me understand how you think this through.

Dr Yaghmour:
After the FDA approves a treatment, I think many of us rely on the Prescribing Information and the studies supporting its approval to determine its appropriate use. In the case of FABHALTA, I think the guidance is clear: FABHALTA is approved for adult patients with PNH, whether it’s someone who’s starting on their complement inhibitor or switching from a C5i monotherapy.⁵

I think some factors that make me consider patients for FABHALTA are:

• Any adult patients with PNH who have been on C5is who continue having residual anemia (hemoglobin <10 g/dL) despite C5i treatment for at least 6 months⁵
• Complement inhibitor–naive adult patients with PNH because FABHALTA has data for this population as well⁵

I have personally used FABHALTA in my practice, both in complement inhibitor–naive and C5i-switch patients, and I am seeing more cases of patients being on FABHALTA. With each new case, I am more confident in the results a treatment option like FABHALTA can possibly offer my patients.  

Steve Stone:
To clarify, the 2 distinct populations Dr Yaghmour is referring to were studied in the APPLY and APPOINT studies. Both were open-label phase 3 trials.^12,13 

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 24-week, randomized treatment period.

Because this was an international study, it included US-approved and non–USapproved eculizumab or ravulizumab.^5,10 What’s important here is that all 97 patients enrolled 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. The patients were randomized in an 8:5 ratio. So, in total, 62 patients were switched to FABHALTA 200 mg orally twice daily and 35 patients continued on their C5i regimen, 23 patients on eculizumab and 12 patients on ravulizumab.^10,12 

The APPOINT study, on the other hand, enrolled 40 complement inhibitornaive patients with a mean hemoglobin of <10 g/dL and LDH levels >1.5 times the upper limit of normal. There was no control arm. So, all patients received FABHALTA 200 mg orally twice daily for a 24-week core treatment period.^10,13 

Both of these studies shared a common primary end point of the proportion of patients achieving sustained hemoglobin increases of ≥2 g/dL from baseline without a need for RBC transfusions. The APPLY trial had an additional primary end point of the proportion of patients achieving a sustained hemoglobin level of ≥12 g/dL without a need for RBC transfusions.¹⁰ 

Dr Yaghmour:
Personally, I find the results of both the APPLY and APPOINT studies to be quite impressive, especially the hemoglobin results.

Beginning with the APPLY study, here’s what the data tell us:

• After a 24-week, randomized treatment period, significantly more patients achieved hemoglobin improvements in the absence of RBC transfusions with FABHALTA vs C5is¹⁰
• 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%⁵
• For me, it’s worth highlighting that these data show sustainable hemoglobin level increases—something that hematologists historically may have struggled to achieve with other therapies
• I also believe that needing fewer transfusions can have an impact on patients’ day-to-day activities that is worth considering

But here’s an important detail: Hemoglobin increases were measured between Weeks 18 and 24, while the absence of RBC transfusions was tracked from Week 2 all the way to Week 24.¹² So, I think we’re looking at a pretty comprehensive window to understand the impact of switching vs staying the course with C5i in the APPLY study.

Steve Stone:
Yes, and this detail is true for all of the primary end points in both the APPLY and APPOINT studies. Thank you for pointing that out, Dr Yaghmour. What else should we be paying attention to?  

Dr Yaghmour:
For the APPLY study, 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^.5

I like to refer to this as “normalization of hemoglobin levels” because, although normal hemoglobin levels may vary, they’re generally between 12-16 g/dL for women and 13-18 g/dL for men.^14,15  

Steve Stone:
And when we talk about any treatment, it’s not just about efficacy; we also have to consider safety. Because at the end of the day, it’s about balancing benefit and risk.

In terms of safety, in the APPLY study 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.⁵ 

In terms of safety, in the APPLY study, serious adverse reactions were reported in 2 adults, or 3% of patients, on FABHALTA and included pyelonephritis, urinary tract infection, and COVID-19.⁵  Rash was reported in 2 adults, or 3%, of FABHALTA-treated patients.⁵

Regarding FABHALTA-treated patients who had normal platelet counts at baseline, 37 of patients, or 43%, had any grade thrombocytopenia during the randomized treatment period.⁵ Three FABHALTA-treated patients experienced decreased platelets that worsened to grade ≥3 from baseline (1 patient with normal platelets and 1 patient with baseline grade 1 worsening to grade 4; and 1 patient with baseline grade 3 worsening to grade 4).⁵ 

No patients discontinued FABHALTA or C5is due to an adverse reaction during the 24-week, randomized treatment period.⁵  

Dr Yaghmour: 
Yes, and regarding key takeaways of the APPOINT study where we are looking at patients who had previously never received a complement inhibitor, the majority of these complement inhibitor–naive adult patients also experienced hemoglobin improvements of ≥2 g/dL from baseline in the absence of RBC transfusions:⁵ 

• Based on central labs, the response rate was 77.5%⁵
• But in a sensitivity analysis where local labs were included when central labs weren’t available, the number came out to 87.5%⁵ 

Now, for me, the hemoglobin end points in APPLY and APPOINT are both meaningful. It prompted me to think about the notion of stable as not being good enough and to better understand what my patients were experiencing if they couldn’t get their hemoglobin levels up. Safety in the APPOINT population is important too.

Adverse reactions reported in >5% of patients in the 24-week core treatment period included headache in 28% of patients, viral infection in 18% of patients, nasopharyngitis in 15% of patients, rash in 10% of patients, as well as abdominal pain, diarrhea, and lipid disorder in 8% of patients.⁵

Serious adverse reactions were reported in 2, or 5%, of patients and included COVID-19 and bacterial pneumonia.⁵ 

Bacterial infection and nausea were reported in 2 patients (5%), and dizziness and urticaria were each reported in 1 patient (3%).⁵

No patient discontinued FABHALTA due to an adverse reaction in the core treatment period of the APPOINT study.^5,10

In adults with PNH across both studies, the most common adverse reactions (≥10%) with FABHALTA were headache, nasopharyngitis, diarrhea, abdominal pain, bacterial infection, viral infection, nausea, and rash.⁵

Steve Stone:
I would also like to note that because of the risk of serious infections caused by encapsulated bacteria, FABHALTA is only available through a Risk Evaluation and Mitigation Strategy (REMS) program that requires vaccinations.I want to encourage our audience to continue listening to this podcast to hear additional Important Safety Information.

After we hear more about the Important Safety Information, we’ll put this all together and discuss what this means in terms of patient care.

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 are back. So, Dr Yaghmour, what does FABHALTA actually mean, in your opinion, for patient care?

Dr Yaghmour:
In my experience, I am more likely to think about how I can help my patients do more than just get by and hopefully improve their hemoglobin levels, and FABHALTA offers that possibility. Another part about rewiring my mindset is remembering that more options are out there for these patients. FABHALTA has data from the APPLY and APPOINT trials, and I believe I have options to help potentially impact their Hb levels earlier on, as well as the flexibility to choose whether starting them on C5is like eculizumab or ravulizumab vs FABHALTA is appropriate for my complement inhibitor–naive adult patients. Trying a C5i first no longer needs to be the case.

This change in thinking also applies to my current adult patients on eculizumab or ravulizumab. As soon as I see signs of clinically relevant EVH, I start thinking about FABHALTA or other options.  

Steve Stone: 
Right. I’ve made these same personal mindset tweaks myself. An additional one I would add is that with all the options now available, I find that patient input in these decisions is something I can better account for. Any final thoughts here, Dr Yaghmour?  

Dr Yaghmour: 
I think, in PNH, it was a disease where we have had to do our best with what we had and help our patients cope. But now, we have more options available for patients, and that offers more in terms of fitting into their lifestyle  o As a result, I want to encourage my fellow HCPs to not overlook EVH in PNH management. I think it’s important to understand its reported occurrence. I think it’s also important to ask ourselves: Are we recognizing hemoglobin levels under 10 g/dL as being a desirable outcome in some of our patients, depending on their bone marrow status?

That being said, I strongly urge today’s listeners to consider what a treatment choice like FABHALTA may offer to their adult patients with PNH. And also, to listen to their patients, because their voice and choice matters.

Steve Stone:
Thank you, Dr Yaghmour. As we close this episode of “Rewired Thinking,” please continue listening to hear the full FABHALTA Important Safety Information, 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 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.

This program was sponsored by Novartis Pharmaceuticals Corporation. If you missed any part of this discussion, visit ReachMD.com/Industry-Feature. This is ReachMD. Be part of the knowledge.

References:

1. de Castro CM, Patel BJ. Iptacopan for the treatment of paroxysmal nocturnal hemoglobinuria. Expert Opin Pharmacother. 2024;25(18):2331-2339. doi:10.1080/14656566.2024.2404110
2. Soliris. Prescribing information. Alexion Pharmaceuticals, Inc.
3. Ultomiris. Prescribing information. Alexion Pharmaceuticals, Inc.
4. Empaveli. Prescribing information. Apellis Pharmaceuticals, Inc.
5. Fabhalta. Prescribing information. Novartis Pharmaceuticals Corp.
6. PiaSky. Prescribing information. Genentech, Inc.
7. Voydeya. Prescribing information. Alexion Pharmaceuticals, Inc.
8. Waheed A, Shammo J, Dingli D. Paroxysmal nocturnal hemoglobinuria: review of the patient experience and treatment landscape. Blood Rev. 2024;64:101158. doi:10.1016/j.blre.2023.101158
9. Panse J. Paroxysmal nocturnal hemoglobinuria: where we stand. Am J Hematol. 2023;98(suppl):S20-S32. doi:10.1002/ajh.26832
10. 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
11. 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
12. Data on file. Study CLNP023C12302 CSR. Novartis Pharmaceuticals Corp; 2022.
13. Data on file. Study CLNP023C12301 CSR. Novartis Pharmaceuticals Corp; 2022.
14. 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.
15. Cappellini MD, Motta I. 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 

10/25      FA-11367421