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Recent FDA Approval of Danicopan for Patients with PNH

Dr. Caroline Piatek describes the purpose and use of this new drug approval for some patients with PNH, or Paroxysmal Nocturnal Hemoglobinuria.


Leigh Clark:    Hello. Welcome to Podcast for Patients. I'm Leigh Clark, Director of Patient services, and I'll be moderating the podcast today. Before we get started, I'd like to thank our corporate sponsors. Our diamond level sponsors are Alexion and Novartis. Our gold sponsors are Apellis and Genentech. And our bronze sponsor is Regeneron. And thank you also to the patients and families and caregivers for their support of the podcast series.
    Today we're going to be talking with Caroline Piatek, and she is an associate professor of clinical medicine with USC Norris Comprehensive Cancer Center. Welcome, Dr. Piatek. Thank you so much for joining us today.
Caroline Piatek:    Thank you. It's a pleasure to be with you.
Leigh Clark:    Today, we're going to be talking about the recent approval of Danicopan. And, uh, what can you tell us about the recent approval? And what is Danicopan?
Caroline Piatek:    Sure. Danicopan is a first-in-class oral factor D inhibitor. So it's newly approved in the US as add-on therapy to C5 inhibitor therapy with ravulizumab or eculizumab for the treatment of extravascular hemolysis or EVH in adult patients with PNH. So we'll briefly go through a couple of these terms and concepts, and then we'll talk about the clinical trial that led to the approval of Danicopan.
    So as you know, PNH is characterized by the breakdown of red blood cells. This typically occurs within the vessels, and this is called intravascular hemolysis. The red blood cell breakdown in PNH is due to uncontrolled terminal complement activation, and thus PNH therapy is, uh, aimed at blocking complement activity. The complement inhibitor therapies eculizumab and ravulizumab are the mainstays of, uh, therapy of patients with PNH, and they work by blocking terminal complement component 5.
    In trials involving C5 inhibitor therapy, they've been shown to control intravascular hemolysis by reducing LDH, improving hemoglobin, and reducing thrombotic events, leading to decreased morbidity and mortality in people with PNH. However, there are a subset of patients with PNH, that's around 10% to 20%, who experience something called clinically significant extravascular hemolysis while on C5 inhibitor therapy.
    C5 inhibition enables PNH red blood cells to survive, but these surviving still, but these surviving red blood cells are still defective, and they are susceptible to complement destruction, uh, by C3, which is another complement protein. And they're removed by the liver or the spleen. And since the liver and the spleen are outside of the vasculature, this type of hemolysis is called extravascular hemolysis.
    Patients on C5 inhibitor therapy or C5i therapy with EVH may continue to experience anemia and would likely benefit from complement inhibitor therapy higher up or more proximal on the complement pathway. Danicopan is a proximal complement inhibitor. It inhibits complement factor D in the alternative pathway within the complement system. So that's Danicopan background.
    Let's talk about the clinical trial leading to the approval of Danicopan. So this study is called Alpha. It is a global Phase 3 trial designed as a superiority study to evaluate the efficacy and safety of Danicopan as add-on therapy to C5 inhibitor therapy in patients with PNH with clinically significant extravascular hemolysis.
    This is a randomized, placebo controlled, double-blind study. The study included adult patients with PNH who had clinically significant extravascular hemolysis. And this was defined here as a hemoglobin of 10.5 grams or less with an elevated reticulocyte count. So reticulocytes are early red blood cells, and they're a marker of hemolysis. And patients on this study needed to be on ravulizumab or eculizumab for at least six months prior to starting the study.
    Patients were randomized in a two-to-one fashion to receive either Danicopan or placebo in addition to their C5 inhibitor therapy for 12 weeks. For the following 12 weeks of the study, both arms received C5i therapy along with Danicopan, and then after that could continue on to, on this dual therapy for long-term extension.
    The primary endpoint of the study was change in hemoglobin from baseline to week 12. And the key secondary efficacy endpoints were the proportion of participants with a hemoglobin increase of at least two grams or more in the absence of transfusion. Transfusion is key along with changes in fatigue and absolute reticulocyte count from baseline to week 12.
    So today, we'll be talking about the results from the first 63 patients for the first 12 weeks of the study, which was the randomized portion. The baseline hemoglobin in these patients was, uh, 7.61 grams in the Danicopan group and 7.87 in the placebo group. All of the patients in both arms had received a transfusion in the prior six months.
    At week 12, there was a 2.94 gram increase in hemoglobin from the baseline in the Danicopan group compared to placebo. This was statistically significant as well as clinically meaningful. The Danicopan group had statistically significant improvements compared to placebo on all four secondary, uh, endpoints as well.
    So, comparing Danicopan versus placebo at week 12, 60 versus 0% of patients had a increase in hemoglobin of two or more grams in the absence of transfusion. 83 versus 38% had transfusion avoidance. The Danicopan group also had a statistically significant and clinically meaningful improvement in fatigue along with a statistically significant decrease in the absolute reticulocyte count.
    There were no serious adverse events related to Danicopan or death reported in the study, and we'll talk a little bit more about the side effect profile in a minute.
Leigh Clark:    Thank you so much for that, the information A lot of things that happened in the trial that  brought, uh, Danicopan, uh, to approval. who is prescribed Danicopan?
Caroline Piatek:    So Danicopan is approved for patients with PNH on ravulizumab or eculizumab who have extravascular hemolysis. So extravascular hemolysis r- is recognized by ongoing anemia with an elevated reticulocyte count despite control of intravascular hemolysis with C5 inhibitor therapy. Since there are many causes of anemia, anemia from, from extravascular hemolysis should be distinguished from these other causes prior to, uh, initiation of Danicopan.
Leigh Clark:   What are the known side effects? And how is the medication taken by patients?
Caroline Piatek:    So the known side effects of Danicopan, um, include headache. So this was the most common observed side effect in the study, occurring about, in about 10% of patients.
    There also, was noted to be an increase in liver enzymes in the subset of patients, and so this is something that needs to be checked prior to starting Danicopan and then throughout treatment. Then additionally, an increase in lipids was also observed, and so this is another lab to be monitored on Danicopan therapy.
    As with other complement inhibitors, there is an increased risk of infection with encapsulated organisms, and so it's important to be vaccinated for, for those organisms prior to initiation of Danicopan.
    With regards to administration, so again, this is an oral medication. It's taken three times a day. It can be taken with or without food. It's given in addition to ravulizumab or eculizumab, so this approach is called add-on or dual therapy. The initial dose is 150 milligrams a day, or the initial dose is 150 milligrams, which can be increased to 200 milligrams based on clinical response. And as with other therapies for PNH, it's a chronic therapy.
Leigh Clark:    What are the key takeaways from the study that are important for patients to know?
Caroline Piatek:    So this was a positive study. So in patients with PNH with extravascular hemolysis on C5 inhibitor therapy, Danicopan as add-on therapy resulted in clinically meaningful improvements in hemoglobin, improved transfusion avoidance, and improved fatigue.
Leigh Clark:    Thank you so much for sharing all of this great information about this new approval which will give PNH patients more options, and it's certainly going to give their medical providers more options as well for treating PNH. So thank you again for joining us and sharing all this information.
    And if you'd like further information about treatments for PNH, please visit our website, And if you have any questions, please feel free to give us a call at (800)747-2820. Thank you so much for joining us.