Approval of Fabhalta (iptacopan), Oral Medication for Patients with PNH | Aplastic Anemia and MDS International Foundation (AAMDSIF) Return to top.

Approval of Fabhalta (iptacopan), Oral Medication for Patients with PNH

What does this FDA approval mean for patients with PNH?  Find out how this oral medication, Fabhalta, could replace one of the infusion treatments in this interview with Dr. Bart Scott.


Leigh Clark:    Hi, everyone. This is Podcast For Patients with the Aplastic Anemia and MDS International Foundation. I'm Leigh Clark, Director of Patient Services. Our podcast series is brought to you by the generous support of our patients, families, and caregivers just like you and corporate sponsors. Thanks to everyone for supporting the series.
    Today, we're talking about the recent approval of Fabhalta with Dr. Bart Scott from the Fred Hutchinson Cancer Center in Seattle, Washington. Welcome, Dr. Scott.
Bart Scott:    Hello. Thank you for having me and welcome to everyone joining us.
Leigh Clark:    The FDA recently approved Fabhalta for treatment of PNH. What can you tell us about the recent approval?
Bart Scott:    Sure. Fabhalta is also known as iptacopan. It was developed by Novartis. It has a unique mechanism of action. So, it, it actually inhibits what's called Factor B. Factor B is an important part of the complement system, um, and by inhibiting Factor B, you block both proximal and terminal compliment.
    It's not a C5 inhibitor like Ravulizumab-cwvz (Ultomiris) or Eculizumab (Soliris), nor is it a C3 inhibitor like Pegcetacoplan (EMPAVELI). So, it does have a unique mechanism of action. And the other interesting thing about iptacopan or Fabhalta is that it's a pill. So, it is the first medication approved for PNH that's available in an oral format. It's a 200 mg, twice a day, medication.
Leigh Clark:    What are the known side effects?
Bart Scott:    Well, because it inhibits complement, most of the side effects will be related to infections and in fact, there's a black box labeled warning about infectious risk and it'd be primarily the encapsulated organism, so hemacyphulenza B, streptococcus, neisseria, um, all of these are encapsulated organisms. And therefore, it's recommended when possible that patients be vaccinated for these bacterial agents before you begin.
    But if patients are acutely ill, then you start the treatment right away and then vaccinate them at a later time point, but give prophylactic antibiotics.
Leigh Clark:    What should patients expect when starting the new treatment?
Bart Scott:    Great question. So, when someone asks that, I go back to what the clinical trial data is. So, I'll take this opportunity to, to talk about why the drug was approved. Uh, there have been two prospective studies evaluating iptacopan.
    The first one was called the Apply Trial, A-P-P-L-Y. And that was presented last year, not at this year's ASH, but last year's ASH as a late-breaking abstract by Dr. de Latour, that took patients who had PNH, were on treatment with an anti-C5 agent, so that would be Eculizumab (Soliris) or Ravulizumab-cwvz (Ultomiris), but still had what's called clinically significant extravascular hemolysis. And perhaps it's too much for this podcast to go into extravascular versus intravascular hemolysis, but perhaps we could have another discussion about that at a later time point if it's not already been done.
    But these patients had to have clinically significant extravascular hemolysis which was to find a hemoglobin less than 10 and an absolute reticulocyte count greater than 100 times 10 to ninth. So, they had a reticulocytosis and they ongoing anemia, which indicates that they're still have some issues with their PNH. And so the patients were subsequently randomized eight to five; eight patients for every five would receive oral iptacopan and then the five patients would receive the anti-C5 therapy that they were on before.
    So, it was an open-label study. it wasn't double-blinded and there was no placebo control. They received this starting on, on week one. And then at some point they were switched, uh, to oral iptacopan, so everyone got the oral iptacopan in the 24-week extension period. So, the first treatment period w- where they were randomized was 24 weeks and the primary end point of that study was hemoglobin improvement of greater than or equal to two grams per deciliter and also hemoglobin greater than 12 grams per deciliter. So, basically, improvement of the anemia.
    And the study did meet its primary end point. Among the patients who received iptacopan, 82.3% of patients had an increase in their hemoglobin greater than two grams per deciliter. Whereas only 2% in the continued anti-C5 therapy arm did. And then if you look at the hemoglobin greater than or equal to 12, 68.8% in the iptacopan arm, which is what Fabhalta is also called, met the primary end point, whereas only 1.8% in the standard of care arm did. Both of these were statistically significantly different, so the study did meet its primary end point. And compared to Eculizumab (Soliris) or Ravulizumab-cwvz (Ultomiris), more patients had improvement in their hemoglobin with iptacopan.
    But there are some caveats and the biggest caveat is that this was a select patient population who had EBH on anti-C5 therapy that was thought to be clinically significant. And the other big caveat is that many times when people are anti-C5 therapy we increase the dose because they're having some, uh, continued hemolysis. And so one of the weaknesses of these types of studies is that it doesn't allow for pure flexibility in how you give the anti-C5 therapy. So, some might criticize that the control arm was suboptimally delivered; what I like to call suboptimal anti-C5 therapy.
    And then the other trial that, um, has been performed that was important with iptacopan was called the Appoint Trial. Oh, just another criticism about APPLY, it's early follow-up. So, the 24-week data that we have, not the long-term follow-up that you have with Ravulizumab-cwvz (Ultomiris), Eculizumab (Soliris), and Pegcetacoplan (EMPAVELI).
    And then the other trial was the Appoint Trial and in that it was people getting treatment upfront, so there was no randomization. It was newly diagnosed PNH patients. There were 40 of these patients and they received iptacopan, Fabhalta 200 mg, twice a day. And the 24-week endpoint, primary endpoint was a hemoglobin increase. And among the patients, 40 patients who enrolled into the study, um, 92.2% had a hemoglobin increase of greater than 2 grams per deciliter. So that also met the primary end point leading to the approval of this medication. So, it's the first orally-approved therapy for PNH.
    Oh, and to get back to your question, what can they expect for their hemoglobin to go up? For their fatigue to get better, and for the LDH to go down.
Leigh Clark:    Thank you, Dr. Scott. If a patient was interested in switching to this new treatment, what is the process for switching?
Bart Scott:    Well, you want to make sure that there is good overlap between the two therapies. So most of these patients are going to be on Ravulizumab-cwvz (Ultomiris), so you want to give the dose of Ravulizumab-cwvz (Ultomiris) and then start the oral iptacopan, and then with the next dose of Ravulizumab-cwvz (Ultomiris) you would not need to give that, that you want to make sure that you at least have some overlap between the iptacopan, and the Ravulizumab-cwvz (Ultomiris), which is Ultomiris.
Leigh Clark:    Thank you, Dr. Scott. Taking an oral therapy, if a patient were to miss a dose-
Bart Scott:    Mm-hmm.
Leigh Clark:    ... do we know how a patient would react to a missed dose? What should a patient do if they were to miss a dose of the oral medication?
Bart Scott:    Great question. I'm glad that you asked that because I'd like to highlight a very important point about iptacopan. You have to have a very compliant patient because if you take, um, any type of PNH therapy and you miss a dose, you are an extreme risk of having breakthrough intravascular hemolysis.
    The half-life of iptacopan is such that probably you're not going to run in severe issues if you miss one dose, but what should happen is the patient should take the medication as soon as they become aware of the missed dose and then continue on as they normally would.
    You know, that's one of the questions that many of us who deal with patients like this have, um, how many missed doses would it take for someone to have breakthrough IVH?
    Of course, you don't want to do a real-world experiment about that, so we don't ever really want to know the answer to that question, but from my understanding, missing one dose is probably not going to lead to a severe breakthrough IVH because of the, um, half-life of the medication. But it is a twice a day drug and compliance is a very important feature of who should and should not receive this medication.
Leigh Clark:    Is there anything else that you would like patients to know about the new treatment?
Bart Scott:    The route of delivery obviously is a lot better. You don't have to come in for the every six- to eight-week confusion of the Ultomiris. And with Pegcetacoplan (EMPAVELI) of course that's delivered as a subcutaneous infusion.
    So, it does have a better route of delivery, but I also think it's important to know that we have long-term follow-up of the safety and the efficacy of Ravulizumab-cwvz (Ultomiris) and also Pegcetacoplan (EMPAVELI), so it's a newer drug, the early data looks promising, um, and it has a good route of delivery.
Leigh Clark:    Thank you so much, Dr. Scott, for sharing your time and your expertise with all of us, today. If you'd like to find out more about PNH and about treatments for PNH, you can find that information on our website,, or you can give us a call on our help line, which 800-747-2820. This ends our podcast.