FDA Approval of PiaSky for Patients with PNH

Leigh Clark:    Welcome to Podcast for Patients. I'm Leigh Clark, director of patient services. Thank you so much for joining us today. I have the pleasure today of talking with Doctor Carlos De Castro and we're going to be talking about the recent approval of PiaSky for PNH. And before we get started, I'd just like to thank our sponsors, our diamond sponsors, Alexion and Novartis, for supporting the podcast series.
    How are you doing today, Doctor De Castro?
Carlos De Castro:    We are doing fine, Leigh. How are you?
Leigh Clark:    I'm doing well. Thank you so much for joining us today. So what is PiaSky?
Carlos De Castro:    So PiaSky or I, go by the trade name which is crovalimab, is a new, C5 inhibitor, that's been approved for treatment of adults and actually children above the age of 13 for treatment of their PNH.
Leigh Clark:    And how is it given and what are the known side effects?
Carlos De Castro:    So there is a loading dose that's given on days one and two and it's given weekly for four weeks subcutaneously. It's a small volume so patients are taught how to give this at home. Then once that loading dose is in, it can be given once every four weeks, so it's fairly easy to give and fairly easy to administer. Hopefully patients are taught not to have an aversion to needles because it is subcutaneously.
    The side effect profile from it is, again, fairly mild. The typical things we've seen with C5 inhibitors is what we've seen with, uh, with this drug. We always have to be aware that all these inhibitors can lead to an increased risk of developing meningococcal meningitis so everybody has to be vaccinated ahead of time, usually at least two weeks ahead of the start of  the drug. And patients have to be educated about, meningitis and the signs and symptoms and usually they carry a safety card around, in case they do go to the ER so the docs will know what they're looking at also.
    Outside of that, the only other new side effect that we've seen with this drug is in patients who are switching from another C5 inhibitor. And there can be this funny, what we call transient, immune complex formation that is because this binds to a different part of the C5 or complement five molecule. You can get these, I guess, multimers or complexes of antibody, linked to the C5 then another different antibody linking to a different part of it and you get these larger complexes. What that means clinically is that these patients will develop a rash. It's transient, it may itch a little bit but it usually is very mild and self-limited and goes away within a few weeks. So it's not been something we've been overly concerned about the safety of it because of that, although it is an interesting phenomena that we've seen. It doesn't seem to lead to any kidney damage or end organ damage that we've been very thankful about that.
    Otherwise, you know, typical side effects that we see are-are just things like nasopharyngitis, headaches, with it all, really not any different from any other C5 inhibitor.
Leigh Clark:    Can you tell us about the clinical trial that led to the approval?
Carlos De Castro:    There were actually three clinical trials that led to the approval. They were named COMMODORES 1, 2, and 3. They were trials that in one case looked at naïve patients who hadn't gotten any treatment, actually two of them, studies were on naïve patients. One of them randomized the patients to either getting Eculizumab or getting this drug and was COMMODORE 2. The COMMODORE 1 trial was the one that was in Eculizumab-treated patients, and they switched them over.
    All three of them showed great efficacy of the drug and in fact, the COMMODORE 2, which was the one that, was naïve and comparing it to Eculizumab was a non-inferior trial that was just published again, showing a very good response rate in terms of disease control, hemolytic control, we can't say it's superior to Eculizumab because it was non-inferior trial. All we can say it was not in-inferior to Eculizumab. It did about the same as Eculizumab. And, you know, again, that's a good response that we see that most patients will have excellent control of their hemolysis, and will no longer need transfusions, although some may still do that if they develop extravascular hemolysis.
    There are still instances of breakthrough hemolysis, this idea that if you get an infection and you elevate your complement levels too high it overwhelms the drug. And I think that was about 10% in the crovalimab arm and 14% in Eculizumab arm. Again, not a huge difference there, but you just have to be aware that any sort of infection or stress in the body that raises complement levels can sometimes lead to breakthrough hemolysis and a return of dark urine symptoms.
Leigh Clark:    What is the difference between PiaSky and the other C5 inhibitors that are approved for treating PNH?
Carlos De Castro:    So if we look at just the C5 inhibitors, the-the proximal inhibitors, um, which were Eculizumab and Ravulizumab, this antibody binds to a different epitope on C5. It was, ugh, engineered using something called smart technology so that it would, um, be able to circulate in the blood longer which gives it a longer half-life which is why we can give it every four weeks as opposed to Eculizumab. Now, Ravulizumab must be given intravenously every eight weeks now so four weeks, eight weeks, there is a difference there but this one is subcutaneous, small volume so it can be given at home. You don't have to sit in a infusion chair for an hour or however long it takes to give these other drugs. So you can give it at home and it works okay that way. So that's the major difference between them. It's maybe a convenience issue of being able to give a drug at home every four weeks as opposed to coming in every eight weeks.
Leigh Clark:    Thank you. What else is important for patients to know about PiaSky?
Carlos De Castro:    Just it gives them another option in terms of treatment options. And again, I think we just talked about the route of administration that's different so those are the major differences. Again, they all seem to control hemolysis with PNH about equally well. There's still a risk of extravascular hemolysis with the C5 inhibitors, that's different than if you're on a proximal inhibitor. So you know, I think the choices have to be discussed with the doctor in terms of, "Okay, which one is right for me?" And then I don't have any information yet about the cost of the drug since it was just FDA approved a few weeks ago.
    But I think, again, the decision is still in the hands of the doctor and the patient, in terms of preferences and how it fits with their lifestyle.
Leigh Clark:    Thank you so much, Doctor De Castro, for sharing your time and your expertise and informing all of us about the new treatment option available for doctors and patients. If you'd like to learn more about PNH and other treatment options that are available, please visit our website which is aamds.org. Or please give us a call at (800) 747-2820. Thank you again, Doctor De Castro. Have a great day.
Carlos De Castro:    Thank you, Leigh. Take care.