NARRATOR: Hello, today we will be discussing TAKHZYRO, a preventive treatment for hereditary angioedema, or HAE, and how it can help your patients reimagine effective prevention of HAE attacks. TAKHZYRO is indicated for prophylaxis to prevent attacks of HAE in patients 12 years and older. Hypersensitivity reactions have been observed. In case of a severe hypersensitivity reaction, discontinue TAKHZYRO administration and institute appropriate treatment.
DR. JONES: I’m Dr Douglas Jones based in Layton, Utah, and have practiced for 10 years. This presentation is sponsored by Takeda, and I am speaking on behalf of and receiving an honorarium from Takeda. This program is not approved for continuing medical education credit, nor is it intended to be distributed outside the scope of this program. So please refrain from recording any images or discussions during this presentation.
DR. JONES: Today, we will be discussing the impact that HAE attacks can have on your patients. We will discuss how TAKHZYRO, a first-of-its-kind, subcutaneous, self-injectable treatment taken every 2 weeks, can help with HAE attacks. I will also be discussing the final data of TAKHZYRO from a long-term, open-label extension study. But first let’s take a closer look at HAE.
DR. JONES: If you’ve ever treated a patient with HAE, you know that it is an unpredictable disease that has the potential to be life-threatening. It’s rare, occurring in just 1 in 50,000 people, but often being misdiagnosed, it results in significant morbidity and mortality. As its name implies, most patients have a family history of HAE, but for about 25% it manifests as a novel mutation. About half of patients with HAE have their first attack by age 10.
DR. JONES: HAE attacks can be unpredictable and debilitating. Attacks often occur in the arms, legs, hands, feet, and abdomen. For many patients, triggers for these attacks include stress, physical trauma, such as surgery or a dental procedure, infection, or hormonal influence. While all HAE attacks are concerning, ~50% of patients have experienced a laryngeal attack at some point in their lives, which can lead to asphyxiation.
DR. JONES: HAE is different for every patient, and attacks can differ for the same patient. It’s important to note that past attacks do not predict the severity of future attacks, and a laryngeal attack can occur in a patient who has never even had one before. Also, a single attack can occur across multiple sites, with abdominal swells being especially painful for patients.
DR. JONES: A survey of patients with HAE done in the year 2010 showed that patients had an average of 27 attacks per year. Once the attack begins, the symptoms tend to worsen over a period of 24 hours and then subside over a period of 48 to 72 hours. And while every HAE attack is different, as this chart shows, they do tend to follow a similar course and can last up to 5 days and may spread to multiple sites within the body before eventually resolving.
DR. JONES: One thing that helped my understanding of this was contrasting it with the onset and duration of acute hypersensitivity reactions, or anaphylaxis. They reach a peak severity within 5 to 30 minutes but rarely last for several days. A typical HAE attack progresses and resolves slowly, lasting up to 4 to 5 days.
DR. JONES: HAE attacks can lead to hospitalization. In 1 study, over the course of a year, approximately 13% of patients were hospitalized for an average of 1 week, and approximately 14% required intubation following a laryngeal attack. As physicians, our goal is to improve their HAE, and developing a management plan is the first step towards making things better for our patients. Let’s talk about TAKHZYRO now.
DR. JONES: TAKHZYRO is the only every-2-weeks preventive treatment evaluated in one of the largest studies in HAE with the longest active treatment duration. Now in a few minutes, I’ll get into the study design of the pivotal study, as well as the safety and efficacy of TAKHZYRO. But for now, we want to call your attention to the Indication and Important Safety Information.
DR. JONES: TAKHZYRO is indicated for prophylaxis to prevent attacks of hereditary angioedema, or HAE, in patients 12 years and older. Hypersensitivity reactions have been observed. In case of a severe hypersensitivity reaction, discontinue TAKHZYRO administration and institute appropriate treatment.
DR. JONES: The most commonly observed adverse reactions (greater than or equal to 10% and higher than placebo) associated with TAKHZYRO were injection site reactions consisting mainly of pain, erythema, and bruising at the injection site; upper respiratory infection; headache; rash; myalgia; dizziness; and diarrhea were also observed. Less common adverse reactions observed included elevated levels of transaminases; one patient discontinued the trial for elevated transaminases.
DR. JONES: The safety and efficacy of TAKHZYRO in pediatric patients less than 12 years of age have not been established. No data are available on TAKHZYRO in pregnant women. No data are available on the presence of lanadelumab in human milk or its effects on breastfed infants or milk production.
DR. JONES: To report suspected adverse reactions, contact Dyax Corporation, a Takeda company, at 1-877-Takeda-7, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. For additional Important Safety Information, please see the full Prescribing Information available to you.
DR. JONES: Some of you have not prescribed TAKHZYRO yet. It is an every 2-weeks, preventive, subcutaneous, non–plasma-derived treatment for HAE attacks that requires no reconstitution. For the majority of patients, it took 1 minute or less to self-inject in the clinical trial.
DR. JONES: The recommended starting dose is 300 mg every 2 weeks. TAKHZYRO every 4 weeks is also effective and may be an option if the patient is well-controlled, for example, attack-free, for more than 6 months. Reaching steady-state usually takes about 70 days, or after about 6 doses.
DR. JONES: It’s important to remind your patients to always have an acute treatment on hand and periodically check to ensure it’s not expired. Patients can choose to inject in their abdomen, either thigh, or either arm, depending on which site they prefer. Now, let’s discuss the safety and efficacy of TAKHZYRO through the lens of the HELP study.
DR. JONES: First, let’s talk a little bit about the study population of the pivotal HELP study—this is the clinical study that resulted in FDA approval of TAKHZYRO in 2018. The HELP study was one of the largest studies conducted in the HAE population, with the longest active treatment duration. One hundred twenty-five patients with type 1 or type 2 HAE were treated for 6.5 months.
DR. JONES: As you can see, the pivotal study enrolled a patient population that had a range of characteristics, including a variety of treatment histories: patients who were previously treated with long-term preventive therapy; patients who were taking C1-INH alone; patients who were taking an oral androgen or antifibrinolytic, and even some patients who were treated with both. More than half of patients studied also had 3 or more attacks per month during the run-in period. What you see here is the study design for the HELP study. So let's take a closer look.
DR. JONES: In the HELP study, patients underwent a 4-week run-in period to determine their baseline attack rate. This was preceded by at least a 2-week washout of any long-term prophylactic therapy, if applicable. Eligible patients were randomized 2:1 to receive TAKHZYRO or placebo. Patients randomized to receive TAKHZYRO were assigned in a 1:1:1 ratio of 1 of 3 dosing regimens: 150 mg every 4 weeks, 300 mg every 4 weeks, or 300 mg every 2 weeks. At the end of the 26-week treatment period, patients could enter either an open-label extension study, in which safety was the primary endpoint, or an 8-week safety follow-up. We’ll discuss additional information about the open-label extension study in just a bit.
DR. JONES: For patients with HAE, a strong demonstration of attack reduction is critical. For the primary endpoint of the HELP study, TAKHZYRO offered a significant reduction in attacks compared with placebo. As you can see, patients receiving placebo had almost 2 monthly attacks, on average, from Day 0 to Day 182, or the end of the trial. Patients receiving TAKHZYRO 300 mg every 2 weeks had an attack rate of 0.26, or less than 1 attack per month, on average.
DR. JONES: So, what does this mean? TAKHZYRO demonstrated an 87% reduction in attacks for patients treated with the 300 mg every-2- weeks regimen. There was also a 73% attack reduction in the every-4-weeks regimen.
DR. JONES: These bar charts demonstrate the secondary endpoints of the HELP study: reduction of moderate or severe attacks, as well as reduction of attacks requiring acute treatment. You can see in the left chart that the percentage of reduction of moderate or severe attacks is 83% for patients who received TAKHZYRO 300 mg every 2 weeks and 73% for those that received TAKHZYRO 300 mg every 4 weeks vs placebo.
DR. JONES: The reduction in the least squares mean monthly rate of attacks requiring acute treatment vs placebo was 87% with TAKHZYRO 300 mg every 2 weeks and 74% with TAKHZYRO 300 mg every 4 weeks. So, what percentage of patients in the HELP study achieved zero attacks?
DR. JONES: In a prespecified exploratory endpoint, 44% of patients on TAKHZYRO every 2 weeks experienced 0 attacks compared with only 2% in the placebo group throughout the entire 6-month treatment period. In the HELP study, the number of patients without attacks greatly increased when TAKHZYRO reached its steady-state. Now remember, patients can expect to reach steady-state by their sixth dose (70 days after starting treatment).
DR. JONES: Once patients reached this steady-state period, a post-hoc analysis showed 77% of patients taking TAKHZYRO every 2 weeks had zero attacks for the last 4 months of this study, compared with only 3% in the placebo group. The most common adverse reactions, meaning those occurring in 10% or more of patients, are seen in this table. Injection site reactions were the most common adverse reaction, which includes pain, erythema, and bruising. No incidents of anaphylaxis were reported in the clinical trial.
DR. JONES: It’s important to note that hypersensitivity reactions have been observed. In case of a severe hypersensitivity reaction, discontinue TAKHZYRO administration and institute appropriate treatment. There are no contraindications with TAKHZYRO. One patient, who received 300 mg every 2 weeks, reported 2 hypersensitivity reactions, with symptoms of mouth tingling and pruritus, considered by the investigator to be related to the treatment. These were mild and moderate in intensity, respectively. The patient remained on therapy and enrolled in the open-label extension study. No laboratory abnormalities or presence of antidrug antibodies in this patient were detected at the time of the final analysis of the extension study.
DR. JONES: Less common adverse reactions were observed as well. Other adverse reactions that occurred at a higher incidence in patients treated with TAKHZYRO, compared with placebo, included hypersensitivity, increased AST, and increased ALT. The number of patients treated with TAKHZYRO who experienced maximum transaminase levels greater than 8, 5, or 3 times the upper limit of normal was respectively 1, 0, or 3, compared to 0 in patients treated with placebo. These elevations were asymptomatic and transient. No patients had elevated total bilirubin greater than 2 times the upper limit of normal. One patient treated with TAKHZYRO permanently discontinued treatment due to the elevated transaminases that were considered related to treatment.
DR. JONES: Something very exciting that I can share with you today are the final results from the HELP open-label extension study, or OLE for short. I mentioned them earlier on the study design page, but now let’s go into a little bit more detail about the TAKHZYRO long-term open-label extension data. The open-label extension study evaluated 212 patients for up to 2.5 years. This is significant because this is one of the longest studies ever conducted in HAE, and the results help us see what may be possible when it comes to long-term safety and efficacy.
DR. JONES: There were 109 rollover patients from the HELP study, meaning 97% of patients in the first study decided to continue into the open-label extension study. There were also 103 nonrollover patients. Patients were studied for up to 2-and-a-half years and given TAKHZYRO 300 mg every 2 weeks, for a mean treatment duration of about 30 months. The patient population was also very similar to the first clinical study encompassing a range of treatment histories and attack severities. Here, you’ll see the details of the open-label patient population. So let's take a closer look.
DR. JONES: As I mentioned, there were 109 rollover and 103 nonrollover patients in the open-label extension study. The baseline attack rate of the clinical study was used as baseline for rollover patients, whereas baseline for nonrollover patients was defined as the number of investigator-confirmed attacks reported in the last 3 months. Rollover patients were given a single dose of TAKHZYRO 300 mg and were followed until their first HAE attack. And now at that point, they were given TAKHZYRO 300 mg every 2 weeks for open-label treatment. Meanwhile, nonrollover patients underwent a 4-week washout screening process. After this, they were also given TAKHZYRO 300 mg every 2 weeks for open-label treatment.
DR. JONES: Unlike the HELP study, efficacy was not the primary endpoint in the open-label extension study. Instead, the primary objective of the open-label extension study was to evaluate long-term safety of repeated subcutaneous administrations of TAKHZYRO. All long-term efficacy measures were secondary endpoints.
DR. JONES: Additionally, prespecified exploratory endpoints consisted of the percentage of attack-free days and the percentage of patients who had zero attacks. The data we’ll see on the following slides are all from the open-label extension study.
DR. JONES: So let's examine the efficacy results, which were the secondary and prespecified exploratory endpoints of the OLE study. So attack reduction was consistent with the pivotal trial. TAKHZYRO helped patients reduce attacks by 87% compared with baseline. Moreover, the median monthly attack rate was 0.05 compared with baseline.
DR. JONES: Much like the pivotal study, patients on TAKHZYRO experienced an 84% reduction in moderate or severe attacks and a 93% reduction in attacks requiring acute treatment. As mentioned, the results are consistent with what was seen in the pivotal trial. Did patients achieve 0 attacks for periods of time? Eight out of 10 patients—or 81.8% to be exact—had 0 attacks for at least a 6-month period. On average, patients also experienced 0 attacks for 98% of days during the treatment period.
DR. JONES: Moreover, safety data from the open-label extension study were consistent with the pivotal trial. You can see that injection site pain and viral upper respiratory tract infection were the most common adverse reactions. Hypersensitivity reactions were reported in 2% of patients in the long-term study. Six patients discontinued due to treatment-emergent adverse events. No treatment-related serious adverse events or anaphylaxis were observed in the study. As we near the end of this presentation, let’s recap what we’ve learned about TAKHZYRO.
DR. JONES: As someone who treats a number of patients with HAE, helping them find a preventive treatment that aligns with their goals is my primary objective. That’s why I consider TAKHZYRO for many of my patients with HAE. As we discussed, TAKHZYRO is an every-2-weeks treatment evaluated in one of the largest prevention studies in HAE with over 200 patients and the longest active treatment duration at 2.5 years.
DR. JONES: A significant reduction in the mean attack rate was seen in the pivotal trial and was repeated in the open-label extension study, demonstrating the possibility of zero attacks for periods of time. Long-term safety was also consistent with the results from the pivotal study.
DR. JONES: It’s also worth noting that Takeda offers the Quick Start Program, which provides eligible patients with immediate access to TAKHZYRO at no cost during potential delays during the insurance approval process. So, as the data have shown, TAKHZYRO may be an appropriate preventive treatment option for your patients with HAE.
DR. JONES: Now in my personal experience, TAKHZYRO has helped me rethink the way I treat HAE. The efficacy data that TAKHZYRO has shown, along with its 2-week dosing frequency with 2-mL injections, has helped me and my patients approach preventive treatment in a different way and rethink the possibilities. When I start my patients on TAKHZYRO, I share with them that they may see some attack reduction at first, and they may be using their acute treatments less. But, they may need several weeks and several doses, usually 6 doses, to reach what’s called steady-state.
DR. JONES: As someone who treats a number of patients with HAE, helping them find a preventive treatment that aligns with their treatment goals is my primary objective. That’s why I consider TAKHZYRO for many of my patients with HAE. I believe that the availability of an HAE treatment option such as TAKHZYRO, with its safety and efficacy data and dosing schedule of a 2-mL injection every 2 weeks, has helped me reimagine the way I treat patients with HAE. For additional Important Safety Information, please see the full Prescribing Information available to you. Thank you for joining me for today’s discussion. I hope you found it educational and enjoyable.
NARRATOR: TAKHZYRO is indicated for prophylaxis to prevent attacks of hereditary angioedema, or HAE, in patients 12 years and older. Hypersensitivity reactions have been observed. In case of a severe hypersensitivity reaction, discontinue TAKHZYRO administration and institute appropriate treatment.
NARRATOR: The most commonly observed adverse reactions (greater than or equal to 10% and higher than placebo) associated with TAKHZYRO were injection site reactions consisting mainly of pain, erythema, and bruising at the injection site; upper respiratory infection; headache; rash; myalgia; dizziness; and diarrhea were also observed. Less common adverse reactions observed included elevated levels of transaminases; one patient discontinued the trial for elevated transaminases.
NARRATOR: The safety and efficacy of TAKHZYRO in pediatric patients less than 12 years of age have not been established. No data are available on TAKHZYRO in pregnant women. No data are available on the presence of lanadelumab in human milk or its effects on breastfed infants or milk production.
NARRATOR: To report suspected adverse reactions, contact Dyax Corporation, a Takeda company, at 1-877-Takeda-7, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. For additional Important Safety Information, please see the full Prescribing Information available to you.