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Learn from fellow clinicians who are experienced in treating atypical-HUS.
Physicians are paid consultants for Alexion, and they have been compensated for their time.

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Expert discussion on transitioning to ULTOMIRIS

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Video Transcript

Host:

Welcome to our program, “Transitioning patients with atypical-HUS from eculizumab to ULTOMIRIS (ravulizumab-cwvz),” by Alexion AstraZeneca Rare Disease.

INDICATION

ULTOMIRIS is indicated for the treatment of adults and pediatric patients one month of age and older with atypical hemolytic uremic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy (TMA).

Limitation of Use:

ULTOMIRIS is not indicated for the treatment of patients with Shiga toxin E. coli related hemolytic uremic syndrome (STEC-HUS).

SELECT IMPORTANT SAFETY INFORMATION
WARNING: SERIOUS MENINGOCOCCAL INFECTIONS

Life-threatening meningococcal infections/sepsis have occurred in patients treated with ULTOMIRIS. Meningococcal infection may become rapidly life-threatening or fatal if not recognized and treated early.

  • Comply with the most current Advisory Committee on Immunization Practices (ACIP) recommendations for meningococcal vaccination in patients with complement deficiencies.
  • Immunize patients with meningococcal vaccines at least 2 weeks prior to administering the first dose of ULTOMIRIS, unless the risks of delaying ULTOMIRIS therapy outweigh the risk of developing a meningococcal infection. See Warnings and Precautions for additional guidance on the management of the risk of meningococcal infection.
  • Vaccination reduces, but does not eliminate, the risk of meningococcal infections. Monitor patients for early signs of meningococcal infections and evaluate immediately if infection is suspected.

ULTOMIRIS is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS). Under the ULTOMIRIS REMS, prescribers must enroll in the program. Enrollment in the ULTOMIRIS REMS program and additional information are available by telephone: 1-888-765-4747 or at www.ultomirisrems.com.

Please see additional Important Safety Information for ULTOMIRIS at the end of the program.

ULTOMIRIS is the first and only long-acting medication for the treatment of atypical hemolytic uremic syndrome, or atypical-HUS, in adults and pediatric patients 1 month of age and older.

Like eculizumab, ULTOMIRIS binds to C5 in the bloodstream, although ULTOMIRIS binds to FcRn with greater affinity.

ULTOMIRIS uses FcRn to recycle back to the bloodstream, leaving C5 to be degraded by the lysosome.

Through these modifications, ULTOMIRIS has a half-life approximately 4 times that of eculizumab.

ULTOMIRIS provides immediate, complete, and sustained inhibition of C5 for up to 8 weeks for patients with atypical-HUS.

Our program features Dr Jorge Leguizamo, a hematology specialist with more than 26 years of experience, and…

...Dr Patrick Foy, a specialist in hematology, including the treatment of bleeding and clot disorders.

Dr Leguizamo and Dr Foy have collectively treated or been consulted on more than 50 patients diagnosed with atypical-HUS.

They are paid consultants for Alexion and have been compensated for their time.

Hello, Dr Foy, and hello, Dr Leguizamo. Thank you for joining us today to talk about transitioning from eculizumab to ULTOMIRIS.

In your experience, which patients should be considered for transitioning from eculizumab to ULTOMIRIS?

Dr Leguizamo:

There are two distinct groups.

First, there are patients who have been on eculizumab for months or years.

Then there are the patients who were started on eculizumab when they were hospitalized or patients who have just been discharged from the hospital on eculizumab and are now in the outpatient setting.

Or it might be patients who were just diagnosed with atypical-HUS and treated with eculizumab.

These are all patients who have had a few infusions.

I look to transition every appropriate patient, which will be almost all of them.

Dr Foy:

For me, every patient with atypical-HUS should be considered as a candidate for ULTOMIRIS.

It’s not during every visit with every patient, but I do have the transition conversation with all my patients with atypical-HUS.

Host:

How do you discuss the opportunity to transition to ULTOMIRIS?

Dr Leguizamo:

The range of clinical understanding can vary between patients.

I always cover how ULTOMIRIS is long-acting, built on the foundation of eculizumab, ULTOMIRIS’s safety profile, and that there could be up to 8 weeks between infusions.

Patients and caregivers have the same concerns, such as safety, monitoring, and a fallback plan in case it doesn’t work.

We also talk about possible adverse events or infusion-related reactions.

Dr Foy:

I have the same conversation with caregivers and patients – either together or separately.

Patients may or may not process all the scientific terms, but they know that they are seriously ill and the importance of this decision. We discuss efficacy and safety. I also talk about my experience with patients who have been transitioned. Some patients have shared with me that after transitioning to ULTOMIRIS, they have had more freedom to live their lives in between infusions. Of course, this will vary from patient to patient. There is an emotional component, particularly with patients who have been on eculizumab for a longer period of time. The prospect of transitioning to a new drug can raise questions with patients because they have already been on eculizumab for a number of months or years.

I remind my patients that ULTOMIRIS was built off the backbone of eculizumab.

Host:

What are the first steps in the transition process?

Dr Leguizamo:

We are very familiar with the steps.

Discuss transitioning with the patient and obtain consent; evaluate the patient prior to transitioning.

Before starting the therapy, check and update the appropriate vaccinations.

You will want to keep in mind that ULTOMIRIS has weight-based dosing.

Dr Foy:

For all of my patients who have transitioned from eculizumab to ULTOMIRIS, they all have told me that transition has not been difficult on the logistical end.

We want to make this decision with them. So, we talk about clinical information and aspects of the treatment that are specific to that individual.

Host:

For patients transitioning from eculizumab to ULTOMIRIS, the loading dose of ULTOMIRIS is administered 2 weeks after the last eculizumab infusion.

Maintenance doses are continued once every 8 weeks or every 4 weeks depending on body weight, starting 2 weeks after the loading dose.

The dosing schedule is allowed to occasionally vary within 7 days of the scheduled infusion day except for the first maintenance dose of ULTOMIRIS.

But the subsequent doses should be administered according to the original schedule.

How would you characterize your interactions with atypical-HUS patients during the transition?

Dr Leguizamo:

Patients are rightfully concerned about any changes to their health during the transition.

Monitoring the patient closely is especially important early on.

Dr Foy:

Patients are used to a lot of interaction because of the every-2-week infusion schedule of eculizumab.

The first weeks of the transition should be monitored closely, knowing that once ULTOMIRIS is started, we might see the patient every 8 weeks.

Host:

Under the ULTOMIRIS REMS, prescribers must enroll in the program due to the risk of meningococcal infections.

How does the ULTOMIRIS REMS fit in the transition process?

Dr Leguizamo:

The ULTOMIRIS Risk Evaluation and Mitigation Strategy, or REMS, provides clear guidance and is simple to execute.

Under the ULTOMIRIS REMS, prescribers counsel patients about the risk of meningococcal infections, provide the patients with educational materials, and ensure that patients arevaccinated.

It’s very easy to enroll.

Host:

You have consulted with physicians who are hesitant to transition their patients with atypical-HUS to ULTOMIRIS. What advice do you have for your colleagues?

Dr Foy:

My first response is to point out that we have the data. The trials have shown that ULTOMIRIS has a strong safety and efficacy profile.

Then, you can’t underestimate the impact the 8-week interval has on patients’ lives.

Many patients of mine who’ve transitioned from eculizumab to ULTOMIRIS have shared with me that they have had more time for their family and favorite activities.

We had an opera singer who constantly traveled to performances. This meant he had to find an infusion center every 2 weeks, which was tough.

You can imagine how much easier it was for him when he moved to the 8-week interval.

Dr Leguizamo:

Thank you, Dr Foy and Dr Leguizamo, for sharing your candid insights.

I’d like to remind our listeners of the primary steps in transitioning from eculizumab to ULTOMIRIS.

When considering a transition for your patient with atypical-HUS, be sure to evaluate the patient…

…and take time to educate them about the safety and efficacy of ULTOMIRIS. After discussing transitioning with the patient and obtaining their consent, ensure ULTOMIRIS is available and covered by the patient’s insurance. Confirm the appropriate ULTOMIRIS dose and schedule based on the patient’s body weight. Vaccinate the patient for meningococcal disease according to ACIP guidelines. Set an appointment for 2 weeks after the last dose of eculizumab to begin the first dose of ULTOMIRIS. Provide 2 weeks of antibacterial drug prophylaxis to the patient if ULTOMIRIS must be initiated immediately or vaccines are to be administered less than 2 weeks before starting ULTOMIRIS therapy. And remember, personalized patient support is always available through OneSource™.

I trust the data behind the 8-week frequency. Patients may or may not care about data. They do care about the possibility of 8 weeks vs 2 weeks.

We had sisters who took public transportation every 2 weeks to get their infusion of eculizumab.

It was such a relief for the sisters to move to once every 8 weeks, and it also had the benefit of giving us more time to spend with other patients.

Host:

Thank you, Dr Foy and Dr Leguizamo, for sharing your candid insights.

I’d like to remind our listeners of the primary steps in transitioning from eculizumab to ULTOMIRIS.

When considering a transition for your patient with atypical-HUS, be sure to evaluate the patient…

…and take time to educate them about the safety and efficacy of ULTOMIRIS.

After discussing transitioning with the patient and obtaining their consent, ensure ULTOMIRIS is available and covered by the patient’s insurance.

Confirm the appropriate ULTOMIRIS dose and schedule based on the patient’s body weight.

Vaccinate the patient for meningococcal disease according to ACIP guidelines.

Set an appointment for 2 weeks after the last dose of eculizumab to begin the first dose of ULTOMIRIS.

Provide 2 weeks of antibacterial drug prophylaxis to the patient if ULTOMIRIS must be initiated immediately or vaccines are to be administered less than 2 weeks before starting ULTOMIRIS therapy.

And remember, personalized patient support is always available through OneSource™.

SELECT IMPORTANT SAFETY INFORMATION (CONTINUED)

CONTRAINDICATIONS

  • Patients with unresolved Neisseria meningitidis infection.
  • Patients who are not currently vaccinated against Neisseria meningitidis, unless the risks of delaying ULTOMIRIS treatment outweigh the risks of developing a meningococcal infection.

WARNINGS AND PRECAUTIONS
Serious Meningococcal Infections

Risk and Prevention

Life-threatening meningococcal infections have occurred in patients treated with ULTOMIRIS. The use of ULTOMIRIS increases a patient’s susceptibility to serious meningococcal infections (septicemia and/or meningitis). Meningococcal disease due to any serogroup may occur.

Vaccinate or revaccinate for meningococcal disease according to the most current ACIP recommendations for patients with complement deficiencies. Immunize patients without history of meningococcal vaccination at least 2 weeks prior to the first dose of ULTOMIRIS. If ULTOMIRIS must be initiated immediately in an unvaccinated patient, administer meningococcal vaccine(s) as soon as possible and provide 2 weeks of antibacterial drug prophylaxis. The benefits and risks of antibiotic prophylaxis for prevention of meningococcal infections in patients receiving ULTOMIRIS have not been established. Consider discontinuation of ULTOMIRIS in patients who are undergoing treatment for serious meningococcal infection.

REMS
Under the ULTOMIRIS REMS, prescribers must enroll in the program due to the risk of meningococcal infections. Prescribers must counsel patients about the risk of meningococcal infection/sepsis, provide the patients with the REMS educational materials, and ensure patients are vaccinated with meningococcal vaccines.

Other Infections
Patients may have increased susceptibility to encapsulated bacteria infections, especially infections caused by Neisseria meningitidis but also Streptococcus pneumoniae, Haemophilus influenzae, and to a lesser extent, Neisseria gonorrhoeae. Children treated with ULTOMIRIS may be at increased risk of developing serious infections due to Streptococcus pneumoniae and Haemophilus influenzae type b (Hib). Administer vaccinations for the prevention of Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) infections according to ACIP guidelines. If ULTOMIRIS is administered to patients with active systemic infections, monitor closely for worsening infection.

Monitoring Disease Manifestations after ULTOMIRIS Discontinuation
ULTOMIRIS treatment of aHUS should be a minimum duration of 6 months. Due to heterogeneous nature of aHUS events and patient-specific risk factors, treatment duration beyond the initial 6 months should be individualized. There are no specific data on ULTOMIRIS discontinuation. After discontinuing treatment with ULTOMIRIS, patients should be monitored for clinical symptoms and laboratory signs of TMA complications for at least 12 months.

TMA complications post-discontinuation can be identified if any of the following is observed: Clinical symptoms of TMA include changes in mental status, seizures, angina, dyspnea, thrombosis or increasing blood pressure. In addition, at least two of the following laboratory signs observed concurrently and results should be confirmed by a second measurement 28 days apart with no interruption: a decrease in platelet count of 25% or more as compared to either baseline or to peak platelet count during ULTOMIRIS treatment; an increase in serum creatinine of 25% or more as compared to baseline or to nadir during ULTOMIRIS treatment; or, an increase in serum LDH of 25% or more as compared to baseline or to nadir during ULTOMIRIS treatment. If TMA complications occur after discontinuation, consider reinitiation of ULTOMIRIS treatment or appropriate organ-specific supportive measures.

Thromboembolic Event Management
The effect of withdrawal of anticoagulant therapy during treatment with ULTOMIRIS has not been established. Treatment should not alter anticoagulant management.

Infusion-Related Reactions
Administration of ULTOMIRIS may result in infusion-related reactions including anaphylaxis and hypersensitivity reactions including anaphylaxis and hypersensitivity reactions. In clinical trials, 4 out of 309 patients treated with ULTOMIRIS experienced infusion-related reactions (lower back pain, drop in blood pressure, elevation in blood pressure and limb discomfort) during ULTOMIRIS administration which did not require discontinuation. Interrupt infusion and institute supportive measures if signs of cardiovascular instability or respiratory compromise occur.

ADVERSE REACTIONS
Most common adverse reactions in patients with aHUS (incidence ≥20%) were upper respiratory tract infection, diarrhea, nausea, vomiting, headache, hypertension and pyrexia. Serious adverse reactions were reported in 42 (57%) patients with aHUS receiving ULTOMIRIS. The most frequent serious adverse reactions reported in more than 2 patients (2.7%) treated with ULTOMIRIS were hypertension, pneumonia and abdominal pain. In clinical studies, clinically relevant adverse reactions in <10% of patients include viral tonsillitis in adults and viral infection in pediatric patients and in 3% of adult patients include infusion-related reactions and in 3% of adult patients include infusion-related reactions.

Please see full Prescribing Information (UltomirisHCP.com/PI) and Medication Guide for ULTOMIRIS, including Boxed WARNING regarding serious and life-threatening meningococcal infections/sepsis.

Thank you for viewing. We invite you to learn more about ULTOMIRIS at UltomirisHCP.com/aHUS or contact your local ULTOMIRIS sales representative.

Answers to your questions are a phone call or email away! You can connect with a live representative from Alexion at 833-551-2539 or AlexionConnectTeam@alexion.com.

US/ULT-a/0307

Watch two experts in treating atypical-HUS discuss transitioning patients with atypical-HUS from eculizumab to ULTOMIRIS. Collectively these two clinicians have treated or consulted on over 50 patients with atypical-HUS.

Jorge Leguizamo, MD

Georgia Cancer Specialists
Atlanta, GA

Patrick Foy, MD

Medical College of Wisconsin
Milwaukee, WI

Download a brochure summarizing key points from the discussion between Dr Leguizamo and Dr Foy.

Download Brochure

Evolving treatment considerations for patients with atypical-HUS

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Video Transcript

Hello! My name is Dr Ilene Weitz. I'm a professor of medicine at the Jane Anne Nohl Division of Hematology, Keck USC School of Medicine, Los Angeles, California.

For your awareness, I am a speaker for Alexion Pharmaceuticals and compensated for my time.

Today I will provide an overview of the safety and efficacy of ULTOMIRIS, the first long-acting complement inhibitor approved for the treatment of adults and pediatric patients one month of age and older with atypical hemolytic uremic syndrome, or atypical-HUS.

ULTOMIRIS is not indicated for the treatment of patients with Shiga toxin E. coli related hemolytic uremic syndrome (STEC-HUS).

Throughout the program, we will be reviewing Important Safety Information for ULTOMIRIS, including the Boxed WARNING regarding serious and life-threatening infections/sepsis. Please see the accompanying full Prescribing Information provided at this presentation.

I would like to begin by reviewing the Boxed WARNING regarding the risk of serious meningococcal infections.

Life-threatening meningococcal infections/sepsis have occurred in patients treated with ULTOMIRIS. Meningococcal infection may become rapidly life-threatening or fatal if not recognized and treated early.

  • Comply with the most current Advisory Committee on Immunization Practices (ACIP) recommendations for meningococcal vaccination in patients with complement deficiencies.
  • Immunize patients with meningococcal vaccines at least 2 weeks prior to administering the first dose of ULTOMIRIS, unless the risks of delaying ULTOMIRIS therapy outweigh the risk of developing a meningococcal infection. See Warnings and Precautions for additional guidance on the management of the risk of meningococcal infection.
  • Vaccination reduces, but does not eliminate, the risk of meningococcal infections. Monitor patients for early signs of meningococcal infections and evaluate immediately if infection is suspected.

ULTOMIRIS is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS). Under the ULTOMIRIS REMS, prescribers must enroll in the program. Enrollment in the ULTOMIRIS REMS program and additional information are available by telephone: 1-888-765-4747 or at www.ultomirisrems.com.

ULTOMIRIS is contraindicated in:

  • Patients with unresolved Neisseria meningitidis infection.
  • Patients who are not currently vaccinated against Neisseria meningitidis, unless the risks of delaying ULTOMIRIS treatment outweigh the risks of developing a meningococcal infection.

The objectives of this presentation are to:

  • Describe the mechanism by which ULTOMIRIS inhibits terminal complement activity in patients with atypical-HUS;
  • Present the safety and efficacy of ULTOMIRIS in 2 clinical studies of patients with atypical-HUS; and
  • Review important safety information for ULTOMIRIS as well as recommended dosing and administration in patients with atypical-HUS

I would like to begin with some background on atypical-HUS.

The clinical signs and symptoms of atypical-HUS present as thrombotic microangiopathy, or TMA.

TMA is a serious medical condition characterized by microangiopathic hemolytic anemia, thrombocytopenia, and end-organ injury. The most common symptoms are seen in the kidney, central nervous system, gastrointestinal system, lungs, heart, and eyes.

As shown by this Venn diagram, it has become clear that numerous different underlying conditions can result in development of TMA. These conditions can overlap in any one patient, and some TMAs may be unmasked by triggers, such as infection, transplant, hypertension, and pregnancy/post-partum, among others.

As a result, classification of various forms of TMA has moved towards terminology that is based on underlying etiology and pathophysiology.

To distinguish among the various TMAs, laboratory tests are performed; coagulation parameters to identify disseminated intravascular coagulation (or D-I-C) are typically assessed first, as it would exclude other diagnoses. Culture-based assays for Shiga toxin-producing Escherichia coli (or STEC) in patients with diarrhea can clearly identify STEC-HUS. TTP is distinguished from atypical-HUS on the basis of ADAMTS13 testing – abnormal activity (less than 5-10%) is diagnostic of TTP.

Atypical-HUS is a disease caused by uncontrolled complement activation, which results in endothelial damage and progressive organ damage.

The visual shows the complement-mediated damage that occurs to the endothelium, ultimately causing formation of thrombi in small blood vessels throughout the body.

As you know, the complement system is part of the immune system and is important in protecting the body against pathogens.

The complement system can be activated by 3 different pathways, each triggering a process known as the complement cascade. In the final step of this process, the complement protein C5 is converted to C5a and C5b, the latter forming the terminal complex C5b-9, or membrane attack complex (MAC). This complex attacks cell membranes and destroys the infected or foreign cells.

In atypical-HUS, due to genetic abnormalities affecting the complement regulatory proteins or the presence of autoantibodies, the mechanisms that normally regulate the complement system are not functioning properly. The result is a system that is always “on” instead of being switched on and off, causing damage to normal cells.

ULTOMIRIS is an antibody that binds to the terminal complement protein C5, inhibiting its cleavage to C5a and C5b and preventing generation of the MAC.

ULTOMIRIS was built on the foundation of eculizumab. Although both bind to C5, ULTOMIRIS has been engineered to release C5 in the endosome as pH levels drop, leaving C5 to be degraded by the lysosome while allowing ULTOMIRIS to recycle back into the bloodstream via FcRn. ULTOMIRIS has also been engineered to bind to FcRn with greater affinity.

For eculizumab, binding to C5 inhibits FcRn-mediated recycling, leading to its lysosomal degradation along with C5.

Through these modifications, ULTOMIRIS has an approximately 4x longer half-life than eculizumab, and provides immediate, complete, and sustained inhibition of C5 for up to 8 weeks.

WARNINGS AND PRECAUTIONS
Serious Meningococcal Infections

Risk and Prevention

Life-threatening meningococcal infections have occurred in patients treated with ULTOMIRIS. The use of ULTOMIRIS increases a patient’s susceptibility to serious meningococcal infections (septicemia and/or meningitis). Meningococcal disease due to any serogroup may occur.

Vaccinate or revaccinate for meningococcal disease according to the most current ACIP recommendations for patients with complement deficiencies. Immunize patients without history of meningococcal vaccination at least 2 weeks prior to the first dose of ULTOMIRIS. If ULTOMIRIS must be initiated immediately in an unvaccinated patient, administer meningococcal vaccine(s) as soon as possible and provide 2 weeks of antibacterial drug prophylaxis. The benefits and risks of antibiotic prophylaxis for prevention of meningococcal infections in patients receiving ULTOMIRIS have not been established. Consider discontinuation of ULTOMIRIS in patients who are undergoing treatment for serious meningococcal infection.

REMS
Under the ULTOMIRIS REMS, prescribers must enroll in the program due to the risk of meningococcal infections. Prescribers must counsel patients about the risk of meningococcal infection/sepsis, provide the patients with the REMS educational materials, and ensure patients are vaccinated with meningococcal vaccines.

Other Infections
Patients may have increased susceptibility to encapsulated bacteria infections, especially infections caused by Neisseria meningitidis but also Streptococcus pneumoniae, Haemophilus influenzae, and to a lesser extent, Neisseria gonorrhoeae. Children treated with ULTOMIRIS may be at increased risk of developing serious infections due to Streptococcus pneumoniae and Haemophilus influenzae type b (Hib). Administer vaccinations for the prevention of Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) infections according to ACIP guidelines. If ULTOMIRIS is administered to patients with active systemic infections, monitor closely for worsening infection.

How would you describe the mechanism of action of ULTOMIRIS to your patients?

Let’s now review the ULTOMIRIS clinical development program—specifically, the phase 3 studies, 311 and 312.

I’ll begin with the 311 adult trial, which was an open-label, single-arm study conducted in adult patients who were naïve to complement inhibitor treatment prior to study entry. The study consisted of a 26-week Initial Evaluation Period, and patients were allowed to enter an extension period for up to 4.5 years.

A total of 56 adult patients were evaluated for efficacy. Participants were required to have a platelet count ≤150 x 109/L, evidence of hemolysis such as an elevation in serum LDH, and serum creatinine above the upper limits of normal or required dialysis.

Patients with TMA due to ADAMTS13 deficiency, STEC-HUS, and genetic defect in cobalamin C metabolism were excluded.

More than half of patients in study 311 represented a critically ill population.

93% had extra-renal signs or symptoms of atypical-HUS at baseline; 71% had Stage 5 chronic kidney disease (CKD) as assessed by eGFR; 14% had a history of transplant; and 14% had evidence of TMA >3 days after childbirth.

The primary end point was Complete TMA Response during the 26-week Initial Evaluation Period, as evidenced by normalization of hematological parameters (platelet count and LDH) and ≥25% improvement in serum creatinine from baseline. Patients had to meet each Complete TMA Response criterion at 2 separate assessments obtained at least 4 weeks apart and any measurement in between.

Select secondary end points included time to complete TMA response and complete TMA response status over time, dialysis requirement and CKD stage as evaluated by eGFR, and hemoglobin response.

The results of the study are shown here. Slightly more than half of patients, 54%, achieved a complete TMA response during the 26-week Initial Evaluation Period. Platelet count normalized in 84% of patients; LDH normalized in 77% of patients; and 59% of patients had ≥25% improvement in serum creatinine from baseline.

73% of patients had hematologic normalization, which is the combination of platelet count and LDH normalization.

100% of complete TMA responses were maintained through all available follow-up, and greater than 99.5% of all free C5 serum samples showed complete inhibition of C5 throughout the 6-month study period with ULTOMIRIS.

Complete TMA Response was achieved at a median time of 86 days. The median duration of Complete TMA Response was 7.97 months.

Mean platelet count increased from 118.52 × 109/L at baseline to 240.34 × 109/L at Day 8 and remained above 227 × 109/L at all subsequent visits in the Initial Evaluation Period.

Mean eGFR increased from 15.86 mL/min/1.73m2 at baseline to 51.83 mL/min/1.73m2 at all subsequent visits in the Initial Evaluation Period. In patients with Complete TMA Response, renal function continued to improve after the Complete TMA Response was achieved.

17 of the 29 patients, 59%, who required dialysis at study entry discontinued dialysis by the end of the available follow-up; 6 of 27 patients, 22%, who were off dialysis at baseline were on dialysis at last available follow-up.

This slide and the next show the safety of ULTOMIRIS in 58 adult patients diagnosed with atypical-HUS in study 311.

The table presents adverse reactions reported in 10% or more of adult patients who received ULTOMIRIS.

The most frequent adverse reactions reported in ≥20% of adult patients were headache, diarrhea, nausea, upper respiratory tract infection, vomiting, hypertension, and arthralgia.

Serious adverse reactions were reported in 42, or 57%, adults and pediatric patients with atypical-HUS. The most frequent serious adverse reactions reported in more than 2 patients were hypertension, pneumonia and abdominal pain.

Clinically relevant adverse reactions in <10% of="" adult="" patients="" included="" viral="">

Four patients died during study 311. Patient deaths were determined by study investigators as unrelated to study drug.

How do adult patients with atypical-HUS typically present?

Next, I would like to discuss the 312 pediatric trial, which was a 26-week, multicenter, open-label, single-arm study with an optional 4.5-year extension.

14 pediatric patients naïve to eculizumab with documented diagnosis of atypical-HUS were enrolled and included in this analysis. Participants were required to have a platelet count ≤150 x 109/L, evidence of hemolysis such as an elevation in serum LDH, and serum creatinine level ≥97.5% percentile at screening or required dialysis.

Enrollment criteria excluded patients presenting with TMA due to ADAMTS13 deficiency, STEC-HUS, and genetic defect in cobalamin C metabolism.

71% of pediatric patients had extra-renal signs or symptoms of atypical-HUS at baseline; 36% had Stage 5 CKD at baseline as assessed by eGFR; and 7% had a history of prior kidney transplant.

As with the adult study, in the pediatric trial, the primary end point was Complete TMA Response during the 26-week Initial Evaluation Period, as evidenced by normalization of hematological parameters and ≥25% improvement in serum creatinine from baseline. Patients had to meet each Complete TMA Response criterion at 2 separate assessments obtained at least 4 weeks apart and any measurement in between.

Select secondary end points included: time to complete TMA response and complete TMA response status over time, dialysis requirement and CKD stage as evaluated by eGFR, and hemoglobin response.

As you can see, nearly 3 out of 4 pediatric patients, or 71%, achieved a complete TMA response during the 26-week Initial Evaluation Period. Platelet count normalized in 93% of patients; LDH normalized in 86% of patients; and 79% of patients had ≥25% improvement in serum creatinine from baseline.

86% of patients had hematologic normalization.

100% of complete TMA responses were maintained through all available follow-up, and 99.6% of all free C5 serum samples showed complete inhibition of C5 throughout the 6-month study period with ULTOMIRIS.

Complete TMA Response was achieved at a median time of 30 days. The median duration of complete TMA response was 5.08 months.

Mean platelet count increased from 60.50 × 109/L at baseline to 296.67 × 109/L at Day 8 and remained above 296 × 109/L at all subsequent visits in the Initial Evaluation Period.

Mean eGFR increased from 28.4 mL/min/1.73m2 at baseline to 108.0 mL/min/1.73m2 by 26 weeks.

Four of the 5 patients, 80%, who required dialysis at study entry were able to discontinue dialysis after the first month in study and for the duration of ULTOMIRIS treatment. No patient started dialysis during the study.

This slide and the next show the safety of ULTOMIRIS in 16 pediatric patients diagnosed with atypical-HUS in study 312.

The table shows adverse reactions reported in 10% or more of pediatric patients who received ULTOMIRIS.

The most frequent adverse reactions reported in ≥20% of pediatric patients were pyrexia, upper respiratory tract infection, headache, diarrhea, constipation, hypertension, and vomiting.

Once again, serious adverse reactions were reported in 42 (57%) adult and pediatric patients with atypical-HUS receiving ULTOMIRIS. The most frequent serious adverse reactions reported in more than 2 patients (2.7%) treated with ULTOMIRIS were hypertension, pneumonia and abdominal pain.

Clinically relevant adverse reactions in <10% of="" pediatric="" patients="" included="" viral="">

There were no deaths reported in study 312 during the time of this analysis.

What end point of the ULTOMIRIS studies do you find most meaningful for your pediatric patients?

ULTOMIRIS treatment of atypical-HUS should be a minimum duration of 6 months. Due to the heterogeneous nature of atypical-HUS events and patient-specific risk factors, treatment duration beyond the initial 6 months should be individualized.

If the patient discontinues treatment with ULTOMIRIS, patients should be monitored for clinical symptoms and laboratory signs of TMA complications for at least 12 months.

Note that a 13.5-fold higher rate of TMA was seen in patients who discontinued complement inhibitor therapy vs patients who stayed on therapy.

If TMA complications occur after discontinuation, consider reinitiation of ULTOMIRIS treatment or appropriate organ-specific supportive measures.

Monitoring Disease Manifestations after ULTOMIRIS
Discontinuation

ULTOMIRIS treatment of aHUS should be a minimum duration of 6 months. Due to heterogeneous nature of aHUS events and patient-specific risk factors, treatment duration beyond the initial 6 months should be individualized.

There are no specific data on ULTOMIRIS discontinuation. After discontinuing treatment with ULTOMIRIS, patients should be monitored for clinical symptoms and laboratory signs of TMA complications for at least 12 months.

TMA complications post-discontinuation can be identified if any of the following is observed: Clinical symptoms of TMA include changes in mental status, seizures, angina, dyspnea, thrombosis or increasing blood pressure. In addition, at least two of the following laboratory signs observed concurrently and results should be confirmed by a second measurement 28 days apart with no interruption: a decrease in platelet count of 25% or more as compared to either baseline or to peak platelet count during ULTOMIRIS treatment; an increase in serum creatinine of 25% or more as compared to baseline or to nadir during ULTOMIRIS treatment; or, an increase in serum LDH of 25% or more as compared to baseline or to nadir during ULTOMIRIS treatment.

If TMA complications occur after discontinuation, consider reinitiation of ULTOMIRIS treatment or appropriate organ-specific supportive measures.

Thromboembolic Event Management

The effect of withdrawal of anticoagulant therapy during treatment with ULTOMIRIS has not been established. Treatment should not alter anticoagulant management.

Infusion-Related Reactions

Administration of ULTOMIRIS may result in infusion-related reactions. In clinical trials, 5 out of 296 patients treated with ULTOMIRIS experienced infusion-related reactions (lower back pain, drop in blood pressure, infusion-related pain, elevation in blood pressure and limbs discomfort) during ULTOMIRIS administration which did not require discontinuation. Interrupt infusion and institute supportive measures if signs of cardiovascular instability or respiratory compromise occur.

ADVERSE REACTIONS

Most common adverse reactions in patients with aHUS (incidence ≥20%) were upper respiratory tract infection, diarrhea, nausea, vomiting, headache, hypertension and pyrexia. Serious adverse reactions were reported in 42 (57%) patients with aHUS receiving ULTOMIRIS. The most frequent serious adverse reactions reported in more than 2 patients (2.7%) treated with ULTOMIRIS were hypertension, pneumonia and abdominal pain. In clinical studies, clinically relevant adverse reactions in <10% of="" patients="" include="" viral="" tonsillitis="" in="" adults="" and="" viral="" infection="" in="" pediatric="">

ULTOMIRIS is dosed based on weight. The recommended dosing regimen for patients with atypical-HUS consists of a loading dose followed by maintenance dosing.

Starting 2 weeks after the loading dose, maintenance doses should be administered once every 8 weeks or every 4 weeks depending on body weight.

For patients switching from eculizumab to ULTOMIRIS, the loading dose of ULTOMIRIS should be administered 2 weeks after the last eculizumab maintenance infusion. Maintenance doses of ULTOMIRIS should then be given once every 8 weeks or every 4 weeks (depending on body weight) starting 2 weeks after the loading dose administration.

Administration of plasmapheresis or plasma exchange, or fresh frozen plasma infusion may reduce ULTOMIRIS serum levels. There is no experience with administration of supplemental doses of ULTOMIRIS.

Be sure to vaccinate patients according to ACIP guidelines to reduce the risk of meningococcal infection.

If you are concerned about public health risks associated with your patients visiting an infusion center often during the current pandemic, consider talking to them about ULTOMIRIS.

Infections, including viral infections, have been shown to amplify complement activity, which could have the potential to exacerbate a patient’s condition in an underlying complement-driven disease.

Patients with atypical-HUS receiving ULTOMIRIS should continue treatment.

The less frequent infusions and visits to hospitals/clinics associated with ULTOMIRIS can potentially reduce exposure of atypical-HUS patients, caregivers, and healthcare staff to high-risk environments by enabling social distancing.

For most patients, the cost of medicine associated with ULTOMIRIS may be less than their current therapy on an ongoing, annual basis.

To summarize, ULTOMIRIS is the first and only long-acting complement inhibitor that provides immediate and complete C5 inhibition sustained for up to 8 weeks in patients with atypical-HUS.

100% of adult and pediatric patients had complete C5 inhibition after the first infusion of ULTOMIRIS.

In clinical studies, the majority of adult and pediatric patients met the composite end point of complete TMA response with ULTOMIRIS by 26 weeks.

ULTOMIRIS demonstrated up to 8 weeks of sustained C5 inhibition and the possibility to live dialysis-free in adult and pediatric patients.

The most common adverse reactions reported in ≥20% of adults and pediatric patients with atypical-HUS treated with ULTOMIRIS were upper respiratory tract infection, diarrhea, nausea, vomiting, headache, hypertension, and pyrexia.

Thank you for learning about atypical-HUS and ULTOMIRIS. Please see the accompanying full Prescribing Information for ULTOMIRIS, including Boxed WARNING regarding serious and life-threatening meningococcal infections/sepsis provided at this presentation. Please contact your Alexion sales representative with any questions or to discuss ULTOMIRIS.

US/ULT-a/0139

Discover the role the complement system plays in the pathophysiology of atypical-HUS from a leading researcher in hematologic disorders. Dr Weitz narrates a virtual presentation about the mechanism by which a C5 inhibitor treats terminal complement activity in patients with atypical-HUS.

Ilene C. Weitz, MD

Keck School of Medicine at the University of Southern California
Los Angeles, CA

Podcasts

Adult case study in transitioning atypical-HUS patients from eculizumab to ULTOMIRIS

Even with a complex case, transitioning to ULTOMIRIS may be an option. Dr George, a Virginia-based hematologist, discusses a case study in transitioning a patient with multiple comorbidities, including atypical-HUS, from eculizumab to ULTOMIRIS.

Listen
19:34
Podcast Transcript
Host:

On behalf of Alexion, welcome to our podcast featuring a case that illustrates the transition of a patient with atypical hemolytic uremic syndrome, or atypical-HUS, from eculizumab to ULTOMIRIS (ravulizumab-cwvz).

INDICATION

ULTOMIRIS is indicated for the treatment of adults and pediatric patients one month of age and older with atypical hemolytic uremic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy (TMA).

Limitation of Use:

ULTOMIRIS is not indicated for the treatment of patients with Shiga toxin E. coli related hemolytic uremic syndrome (STEC-HUS).

SELECT IMPORTANT SAFETY INFORMATION
WARNING: SERIOUS MENINGOCOCCAL INFECTIONS

Life-threatening meningococcal infections/sepsis have occurred in patients treated with ULTOMIRIS. Meningococcal infection may become rapidly life-threatening or fatal if not recognized and treated early.

  • Comply with the most current Advisory Committee on Immunization Practices (ACIP) recommendations for meningococcal vaccination in patients with complement deficiencies.
  • Immunize patients with meningococcal vaccines at least 2 weeks prior to administering the first dose of ULTOMIRIS, unless the risks of delaying ULTOMIRIS therapy outweigh the risk of developing a meningococcal infection. See Warnings and Precautions for additional guidance on the management of the risk of meningococcal infection.
  • Vaccination reduces, but does not eliminate, the risk of meningococcal infections. Monitor patients for early signs of meningococcal infections and evaluate immediately if infection is suspected.

ULTOMIRIS is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS). Under the ULTOMIRIS REMS, prescribers must enroll in the program. Enrollment in the ULTOMIRIS REMS program and additional information are available by telephone: 1-888-765-4747 or at www.ultomirisrems.com.

ULTOMIRIS is the first and only long-acting medication for the treatment of atypical-HUS in adults and pediatric patients one month of age and older.1 As we talk about transitioning, it’s important to keep in mind how ULTOMIRIS differs from eculizumab.

Like eculizumab, ULTOMIRIS binds to C5 in the bloodstream, although ULTOMIRIS binds to FcRn with greater affinity.1-3

For eculizumab, binding to C5 inhibits FcRn-mediated recycling, which means that eculizumab is destroyed when C5 is destroyed.3

ULTOMIRIS uses FcRn to recycle back to the bloodstream, leaving C5 to be degraded by lysosomes.3

Through these modifications, ULTOMIRIS has a half-life of 51.8 days, approximately 4x that of eculizumab, so ULTOMIRIS provides immediate, complete, and sustained inhibition of C5 for up to 8 weeks, compared to 2 weeks with eculizumab.1-3

This increased time between infusions can provide patients with additional freedom to enjoy the things they love.1-3

We are fortunate to be joined today by Dr Edward George.

Co-founder and former leader of Virginia Oncology Associates, Dr George is a board-certified hematology specialist who has treated or been consulted on many patients diagnosed with atypical-HUS.

Dr George is a paid consultant for Alexion and has been compensated for his time.

Welcome, Dr George.

Let’s discuss a patient who received a diagnosis and care from a colleague in your practice.

This case certainly illustrates challenges faced by patients with atypical-HUS and their transition from eculizumab to ULTOMIRIS.

This case is based on an actual patient, but the name has been changed to protect the patient’s privacy.

Dr George, tell us about this patient’s history.

Dr George:

Well, thanks for letting me share this illustrative case.

Andrew’s history included significant issues, beginning early in his adult life.

He was diagnosed with acute end-stage renal disease at age 25; he also suffered a stroke, which caused permanent left visual field cut.

He went on dialysis until he was able to receive a kidney.

Unfortunately, the transplant had to be removed due to immunologic acute humoral rejection, and so Andrew went back on dialysis.

In the process of dialysis, he had 3 arteriovenous fistulas, or AVFs, all of which thrombosed.

At age 34, he received his second kidney transplant but experienced graft-related pain, renal graft failure, and edema.

The pathology of the graft indicated a thrombotic microangiopathy, or TMA.

Following that, he was misdiagnosed with thrombotic thrombocytopenic purpura, or TTP, underwent plasmapheresis and, subsequently, had the second kidney transplant removed because it failed.

Host:

Wow, what an experience this patient had. This really emphasizes the severity of this condition. What happened next?

Dr George:

Andrew is an articulate and persistent advocate for his own health.

Our diagnosis went through the process of elimination.

His blood tests showed ADAMTS13 activity of 100%, which essentially ruled out a TTP.4-6

He also received a negative stool test for Shiga toxin–producing E coli, or STEC.6

These, combined with a reassessment of his lab values and the exclusion of other causes of TMA, indicated the patient had atypical-HUS, and Andrew was started on eculizumab.6 He was immunized with meningococcal vaccines two weeks prior to the administration of his first dose.1

The decision considered the failure of both of his transplants, even with immunosuppression. And considering his 3 AVFs and his stroke, we sought complement inhibition before considering a third transplant.

He subsequently underwent a third renal transplant and has been able to maintain it to the present.

Host:

It would be understandable that many patients and physicians would consider this a noteworthy resolution.

How did the idea of conversion to ULTOMIRIS emerge?

Dr George:

After almost 7 years of being treated with eculizumab, Andrew came to see us for a follow-up visit, and this was about the same time that our practice became aware of the impending approval of ULTOMIRIS.

With ULTOMIRIS for adult patients, infusions are administered once every 8 weeks vs every 2 weeks with eculizumab.1,2

That’s a difference of 6 to 7 times per year vs 26 times per year.

Andrew was briefed on ULTOMIRIS by my colleague, who viewed the possibility of 8 weeks between infusions as an effective alternative to eculizumab.

Then, it all started to come together when ULTOMIRIS was approved.

When Andrew heard of its approval, he requested a thorough discussion of the data, efficacy, safety, and risks.

Host:

Often, a caregiver or loved one is also involved in such a significant decision. Was that the case here?

Dr George:

Yes.

Andrew had a lengthy discussion with his wife, and jointly they concluded that transitioning to this new medication, with its proven efficacy data and well-understood safety and tolerability profile, would be a good choice.1

He also believed that ULTOMIRIS would open up his schedule and create a more convenient, less obligated lifestyle. In his words, it offered him additional freedoms in his life.1

Host:

So, Andrew was then transitioned to ULTOMIRIS.2 Tell us more about that.

Dr George:

His transition to ULTOMIRIS went smoothly, other than early transient headache with the first infusion and tiredness on the day of administration.

His impression of ULTOMIRIS remains positive. And it allows him to get back to doing the things he loves.

Host:

As you reflect on this patient and the transition, what are the lessons learned?

Dr George:

ULTOMIRIS is FDA approved and has an established safety and efficacy profile.1

In our practice, we have successfully transitioned many patients to ULTOMIRIS.

We feel all atypical-HUS patients on eculizumab should be considered for a transition to ULTOMIRIS.

Don’t be surprised when patients say that the ULTOMIRIS 8-week infusion interval for adult atypical-HUS patients, vs 2 weeks with eculizumab, gives them a chance to enjoy more freedoms in life and have more time for their families and favorite activities.1,2

Host:

Thank you, Dr George.

I’d like to remind our listeners of the basic steps in conversion of atypical-HUS patients from eculizumab to ULTOMIRIS.

Evaluate your patient before transitioning.

Educate them about the safety and efficacy of ULTOMIRIS.

Ensure ULTOMIRIS is available and covered by the patient’s insurance.

Confirm the appropriate ULTOMIRIS dose and schedule based on weight.1

Vaccinate for meningococcal disease according to Advisory Committee on Immunization Practices, or ACIP, guidelines.1

Set an appointment for 2 weeks after the last dose of eculizumab to begin the first dose of ULTOMIRIS.1

Provide 2 weeks of antibacterial drug prophylaxis to patients if ULTOMIRIS must be initiated immediately or vaccines are to be administered less than 2 weeks before starting ULTOMIRIS therapy.1

Thank you for listening.

We invite you to learn more about ULTOMIRIS at UltomirisHCP.com/aHUS or contact your local ULTOMIRIS sales representative.

If you are unsure who your local sales representative is, you can reach out to Alexion Connect by phone at 833-551-2539 or email AlexionConnectTeam@alexion.com.

SELECT IMPORTANT SAFETY INFORMATION (CONTINUED)

CONTRAINDICATIONS

  • Patients with unresolved Neisseria meningitidis infection.
  • Patients who are not currently vaccinated against Neisseria meningitidis, unless the risks of delaying ULTOMIRIS treatment outweigh the risks of developing a meningococcal infection.

WARNINGS AND PRECAUTIONS
Serious Meningococcal Infections

Risk and Prevention

Life-threatening meningococcal infections have occurred in patients treated with ULTOMIRIS. The use of ULTOMIRIS increases a patient’s susceptibility to serious meningococcal infections (septicemia and/or meningitis). Meningococcal disease due to any serogroup may occur.

Vaccinate or revaccinate for meningococcal disease according to the most current ACIP recommendations for patients with complement deficiencies. Immunize patients without history of meningococcal vaccination at least 2 weeks prior to the first dose of ULTOMIRIS. If ULTOMIRIS must be initiated immediately in an unvaccinated patient, administer meningococcal vaccine(s) as soon as possible and provide 2 weeks of antibacterial drug prophylaxis. The benefits and risks of antibiotic prophylaxis for prevention of meningococcal infections in patients receiving ULTOMIRIS have not been established. Consider discontinuation of ULTOMIRIS in patients who are undergoing treatment for serious meningococcal infection.

REMS
Under the ULTOMIRIS REMS, prescribers must enroll in the program due to the risk of meningococcal infections. Prescribers must counsel patients about the risk of meningococcal infection/sepsis, provide the patients with the REMS educational materials, and ensure patients are vaccinated with meningococcal vaccines.

Other Infections
Patients may have increased susceptibility to encapsulated bacteria infections, especially infections caused by Neisseria meningitidis but also Streptococcus pneumoniae, Haemophilus influenzae, and to a lesser extent, Neisseria gonorrhoeae. Children treated with ULTOMIRIS may be at increased risk of developing serious infections due to Streptococcus pneumoniae and Haemophilus influenzae type b (Hib). Administer vaccinations for the prevention of Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) infections according to ACIP guidelines. If ULTOMIRIS is administered to patients with active systemic infections, monitor closely for worsening infection.

Monitoring Disease Manifestations after ULTOMIRIS Discontinuation
ULTOMIRIS treatment of aHUS should be a minimum duration of 6 months. Due to heterogeneous nature of aHUS events and patient-specific risk factors, treatment duration beyond the initial 6 months should be individualized. There are no specific data on ULTOMIRIS discontinuation. After discontinuing treatment with ULTOMIRIS, patients should be monitored for clinical symptoms and laboratory signs of TMA complications for at least 12 months.

TMA complications post-discontinuation can be identified if any of the following is observed: Clinical symptoms of TMA include changes in mental status, seizures, angina, dyspnea, thrombosis or increasing blood pressure. In addition, at least two of the following laboratory signs observed concurrently and results should be confirmed by a second measurement 28 days apart with no interruption: a decrease in platelet count of 25% or more as compared to either baseline or to peak platelet count during ULTOMIRIS treatment; an increase in serum creatinine of 25% or more as compared to baseline or to nadir during ULTOMIRIS treatment; or, an increase in serum LDH of 25% or more as compared to baseline or to nadir during ULTOMIRIS treatment. If TMA complications occur after discontinuation, consider reinitiation of ULTOMIRIS treatment or appropriate organ-specific supportive measures.

Thromboembolic Event Management
The effect of withdrawal of anticoagulant therapy during treatment with ULTOMIRIS has not been established. Treatment should not alter anticoagulant management.

Infusion-Related Reactions
Administration of ULTOMIRIS may result in infusion-related reactions including anaphylaxis and hypersensitivity reactions including anaphylaxis and hypersensitivity reactions. In clinical trials, 4 out of 309 patients treated with ULTOMIRIS experienced infusion-related reactions (lower back pain, drop in blood pressure, elevation in blood pressure and limb discomfort) during ULTOMIRIS administration which did not require discontinuation. Interrupt infusion and institute supportive measures if signs of cardiovascular instability or respiratory compromise occur.

ADVERSE REACTIONS
Most common adverse reactions in patients with aHUS (incidence ≥20%) were upper respiratory tract infection, diarrhea, nausea, vomiting, headache, hypertension and pyrexia. Serious adverse reactions were reported in 42 (57%) patients with aHUS receiving ULTOMIRIS. The most frequent serious adverse reactions reported in more than 2 patients (2.7%) treated with ULTOMIRIS were hypertension, pneumonia and abdominal pain. In clinical studies, clinically relevant adverse reactions in <10% of patients include viral tonsillitis in adults and viral infection in pediatric patients and in 3% of adult patients include infusion-related reactions and in 3% of adult patients include infusion-related reactions.

Please see full Prescribing Information (UltomirisHCP.com/PI) and Medication Guide for ULTOMIRIS, including Boxed WARNING regarding serious and life-threatening meningococcal infections/sepsis.

References:
  1. ULTOMIRIS. Prescribing information. Alexion Pharmaceuticals, Inc.; 2021.
  2. SOLIRIS. Prescribing information. Alexion Pharmaceuticals, Inc.; 2020.
  3. Sheridan D, et al. PLoS One. 2018;13(4):e0195909.
  4. Berger B. Clin Kidney J. 2018;12(3):338-347.
  5. Asif A, et al. J Nephrol. 2017;30(3):347-362.
  6. Laurence J, et al. Clin Adv Hematol Oncol. 2016;14(11)(suppl 11):2-15.

Alexion, the Alexion logo, ULTOMIRIS®, and the ULTOMIRIS logo are registered trademarks of Alexion Pharmaceuticals, Inc.

© 2021, Alexion Pharmaceuticals, Inc. All rights reserved.

US/ULT-a/0309

Edward George, MD

Virginia Oncology Associates
Norfolk, VA

Download a printable synopsis of this case study for yourself:

Clinician Case Study

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CASE STUDY FOR YOUR PATIENTS

How ULTOMIRIS works

See how ULTOMIRIS was built on the foundation of eculizumab and how it may be able to widen the world of your patients with atypical-HUS.

Understanding ULTOMIRIS

Discover the ULTOMIRIS difference

Learn what makes ULTOMIRIS different from eculizumab.

Explore the MOA

Additional downloads

Find additional brochures, studies, and information to help you better understand atypical-HUS and treat patients with ULTOMIRIS.

Downloadable materials

INDICATION & IMPORTANT SAFETY INFORMATION

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WARNING: SERIOUS MENINGOCOCCAL INFECTIONS

ULTOMIRIS, a complement inhibitor, increases the risk of serious infections caused by Neisseria meningitidis [see Warnings and Precautions (5.1)] Life-threatening and fatal meningococcal infections 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 vaccination for meningococcal bacteria (for serogroups A, C, W, Y, and B) at least 2 weeks prior to the first dose of ULTOMIRIS, unless the risks of delaying ULTOMIRIS therapy outweigh the risk of developing a serious infection. Comply with the most current Advisory Committee on Immunization Practices (ACIP) recommendations for vaccinations against meningococcal bacteria in patients receiving a complement inhibitor. See Warnings and Precautions (5.1) for additional guidance on the management of the risk of serious infections caused by meningococcal bacteria.
  • Patients receiving ULTOMIRIS are at increased risk for invasive disease caused by Neisseria meningitidis, even if they develop antibodies following vaccination. Monitor patients for early signs and symptoms of serious meningococcal infections and evaluate immediately if infection is suspected.

Because of the risk of serious meningococcal infections, ULTOMIRIS is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called ULTOMIRIS REMS [see Warnings and Precautions (5.2)].

CONTRAINDICATIONS

  • Initiation in patients with unresolved serious Neisseria meningitidis infection.

WARNINGS AND PRECAUTIONS
Serious Meningococcal Infections

ULTOMIRIS, a complement inhibitor, increases a patient’s susceptibility to serious, life-threatening, or fatal infections caused by meningococcal bacteria (septicemia and/or meningitis) in any serogroup, including non-groupable strains. Life-threatening and fatal meningococcal infections have occurred in both vaccinated and unvaccinated patients treated with complement inhibitors.

Revaccinate patients in accordance with ACIP recommendations considering the duration of ULTOMIRIS therapy. 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 ULTOMIRIS therapy is indicated in a patient who is not up to date with meningococcal vaccines according to ACIP recommendations, provide antibacterial drug prophylaxis and administer meningococcal vaccines as soon as possible. Various durations and regimens of antibacterial drug prophylaxis have been considered, but the optimal durations and drug regimens for prophylaxis and their efficacy have not been studied in unvaccinated or vaccinated patients receiving complement inhibitors, including ULTOMIRIS. The benefits and risks of treatment with ULTOMIRIS, as well as those associated with antibacterial drug prophylaxis in unvaccinated or vaccinated patients, must be considered against the known risks for serious infections caused by Neisseria meningitidis.

Vaccination does not eliminate the risk of serious meningococcal infections, despite development of antibodies following vaccination.

Closely monitor patients for early signs and symptoms of meningococcal infection and evaluate patients immediately if 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. Meningococcal infection may become rapidly life-threatening or fatal if not recognized and treated early. Consider interruption of ULTOMIRIS in patients who are undergoing treatment for serious meningococcal infection depending on the risks of interrupting treatment in the disease being treated.

ULTOMIRIS REMS
Due to the risk of serious meningococcal infections, ULTOMIRIS is available only through a restricted program called ULTOMIRIS REMS.

Under the REMS, prescribers must enroll in the REMS, counsel patients about the risk of meningococcal infection, provide patients with the REMS educational materials, assess patient vaccination status for meningococcal vaccines (against serogroups A, C, W, Y, and B) and vaccinate if needed according to current ACIP recommendations two weeks prior to the first dose of ULTOMIRIS.  Antibacterial drug prophylaxis must be prescribed if treatment must be started urgently and the patient is not up to date with both meningococcal vaccines according to current ACIP recommendations at least two weeks prior to the first dose of ULTOMIRIS.  Patients must receive counseling about the need to receive meningococcal vaccines and to take antibiotics as directed, signs and symptoms of meningococcal infection, and be instructed to carry the Patient Safety Card at all times during and for 8 months following ULTOMIRIS treatment.

Further information is available at www.ultomirisrems.com or 1-888-765-4747.

Other Infections
Serious infections with Neisseria species (other than Neisseria meningitidis), including disseminated gonococcal infections, have been reported.

ULTOMIRIS blocks terminal complement activation; therefore, patients may have increased susceptibility to infections, especially with encapsulated bacteria, such as infections caused by Neisseria meningitidis but also Streptococcus pneumoniae, Haemophilus influenzae, and to a lesser extent, Neisseria gonorrhoeae. Children treated with ULTOMIRIS may be at increased risk of developing serious infections due to Streptococcus pneumoniae and Haemophilus influenzae type b (Hib). Administer vaccinations for the prevention of Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) infections according to ACIP recommendations. Patients receiving ULTOMIRIS are at increased risk for infections due to these organisms, even if they develop antibodies following vaccination.

Monitoring Disease Manifestations after ULTOMIRIS Discontinuation
ULTOMIRIS treatment of aHUS should be a minimum duration of 6 months. Due to heterogeneous nature of aHUS events and patient-specific risk factors, treatment duration beyond the initial 6 months should be individualized. There are no specific data on ULTOMIRIS discontinuation. After discontinuing treatment with ULTOMIRIS, patients should be monitored for clinical symptoms and laboratory signs of TMA complications for at least 12 months. TMA complications post-discontinuation can be identified if any of the following is observed: Clinical symptoms of TMA include changes in mental status, seizures, angina, dyspnea, thrombosis or increasing blood pressure. In addition, at least two of the following laboratory signs observed concurrently and results should be confirmed by a second measurement 28 days apart with no interruption: a decrease in platelet count of 25% or more as compared to either baseline or to peak platelet count during ULTOMIRIS treatment; an increase in serum creatinine of 25% or more as compared to baseline or to nadir during ULTOMIRIS treatment; or, an increase in serum LDH of 25% or more as compared to baseline or to nadir during ULTOMIRIS treatment. If TMA complications occur after discontinuation, consider reinitiation of ULTOMIRIS treatment or appropriate organ-specific supportive measures.

Thromboembolic Event Management
The effect of withdrawal of anticoagulant therapy during treatment with ULTOMIRIS has not been established. Treatment should not alter anticoagulant management.

Infusion-Related Reactions
Intravenous administration of ULTOMIRIS may result in systemic infusion-related reactions, including anaphylaxis and hypersensitivity reactions. In clinical trials, infusion-related reactions occurred in approximately 1% of patients treated with ULTOMIRIS.  These events included lower back pain, drop in blood pressure, limb discomfort, drug hypersensitivity (allergic reaction), dysgeusia (bad taste), and drowsiness. These reactions did not require discontinuation of ULTOMIRIS. If signs of cardiovascular instability or respiratory compromise occur, interrupt ULTOMIRIS infusion and institute appropriate supportive measures.

ADVERSE REACTIONS
Most common adverse reactions in patients with aHUS (incidence ≥20%) were upper respiratory tract infection, diarrhea, nausea, vomiting, headache, hypertension and pyrexia. Serious adverse reactions were reported in 42 (57%) patients with aHUS receiving ULTOMIRIS. The most frequent serious adverse reactions reported in more than 2 patients (2.7%) treated with ULTOMIRIS were hypertension, pneumonia and abdominal pain.

Adverse reactions reported in 20% of pediatric patients treated with ULTOMIRIS were diarrhea, constipation, vomiting, pyrexia, upper respiratory tract infection, decreased vitamin D, headache, cough, rash, and hypertension.

DRUG INTERACTIONS
Plasma Exchange, Plasmapheresis, and Intravenous Immunoglobulins
Concomitant use of ULTOMIRIS with plasma exchange (PE), plasmapheresis (PP), or intravenous immunoglobulin (IVIg) treatment can reduce serum ravulizumab concentrations and requires a supplemental dose of ULTOMIRIS.

Neonatal Fc Receptor Blockers
Concomitant use of ULTOMIRIS with neonatal Fc receptor (FcRn) blockers (e.g., efgartigimod) may lower systemic exposures and reduce effectiveness of ULTOMIRIS. Closely monitor for reduced effectiveness of ULTOMIRIS. 

INDICATION
ULTOMIRIS is indicated for the treatment of adult and pediatric patients one month of age and older with atypical hemolytic uremic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy (TMA).

Limitation of Use:
ULTOMIRIS is not indicated for the treatment of patients with Shiga toxin E. coli related hemolytic uremic syndrome (STEC-HUS).

To report SUSPECTED ADVERSE REACTIONS, contact Alexion Pharmaceuticals, Inc. at 1-844-259-6783 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Please see accompanying full Prescribing Information for ULTOMIRIS, including Boxed WARNING regarding serious and life-threatening or fatal meningococcal infections.

Alexion Connect

Healthcare Professionals:
Answers to your questions are
a phone call away! Connect
with a live representative.
833-551-2539

Alexion Connect

Alexion Connect

Healthcare Professionals:
Answers to your questions are
a phone call away! Connect
with a live representative.
833-551-2539

Alexion Connect