ULTOMIRIS, the standard of care for adults with PNH, is now FDA approved for children. Learn More.

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The Science Behind Ultomiris (ravulizumab)

ULTOMIRIS targets C5 and terminal complement1

ULTOMIRIS is designed to provide sustained C5 inhibition and elimination without impacting the essential role of proximal complement in
innate immune system activity1,14,29

ULTOMIRIS is the standard of care for PNH in adults,a designed for extended C5 inhibition and elimination1,6,29

Pharmacology based on preclinical studies of ULTOMIRIS29

aBased on US market share.

bTargeted engineering to incorporate 4 amino acid substitutions designed to reduce target-mediated drug disposition and enhance FcRn-mediated recycling into eculizumab has led to the generation of ULTOMIRIS, which exhibited an extended duration of action in preclinical models relative to eculizumab.

cThe mean (%CV) terminal elimination half-life and clearance of ravulizumab cwvz in patients with PNH are 49.6 (18.3) days and 0.08 (28.1) L/day, respectively. Half-life of eculizumab is 11.25 to 17.25 days.1,30

FcRn=neonatal Fc receptor.

ULTOMIRIS provided immediate, complete, and sustained C5 inhibition in studies of adult and pediatric patients with PNH1,2,5

Free C5 levels below 0.5 μg/mL were correlated with maximal intravascular hemolysis control and complete terminal complement inhibition in clinical studies1

Adult naïve study
Adult switch study
Pediatric study

Complement inhibitor-naïve study4,a-c

Mean free C5 levels over 52 weeks of treatment
Complement inhibitor-naïve study data
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aThe complement inhibitor-naïve study (ALXN1210-PNH-301; NCT02946463) was a 26-week, multicenter, open-label, randomized, active-controlled, noninferiority, phase 3 study with an extension period. Adult patients (N=246) naïve to complement inhibitor treatment prior to study entry were randomized 1:1 to receive ULTOMIRIS or eculizumab. At the end of the randomized period, patients (N=243) entered the extension period, during which all received ULTOMIRIS.

bThe horizontal line in the middle of each box indicates the median, and a diamond indicates the mean. The top and bottom borders of the box represent the 75th and 25th percentiles, respectively, and the whiskers represent the 1.5 interquartile range of the lower and upper quartile. Asterisks represent values outside the interquartile range. Dashed horizontal lines indicate serum free C5 concentration of 0.5 μg/mL.

cA Gyros-based fluorescence assay was used for patients who received ULTOMIRIS, and an electrochemiluminescence immunoassay was used for patients who received eculizumab. Baseline was defined as the last non-missing value before the first dose of study drug.

BL=baseline.

Eculizumab-to-ULTOMIRIS switch study5,a-c

Mean free C5 levels over 52 weeks of treatment
Eculizumab-to-ULTOMIRIS switch study data
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aThe eculizumab-to-ULTOMIRIS switch study (ALXN1210-PNH-302; NCT03056040) was a 26-week, multicenter, open-label, randomized, active-controlled, noninferiority, phase 3 study with an extension period. Adult patients (N=195) who were clinically stable after having been treated with eculizumab for at least the past 6 months were randomized 1:1 to either continue eculizumab or to switch to ULTOMIRIS. At the end of the randomized period, patients (N=191) entered the extension period during which all received ULTOMIRIS.

bThe horizontal line in the middle of each box indicates the median, and a diamond indicates the mean. The top and bottom borders of the box represent the 75th and 25th percentiles, respectively, and the whiskers represent the 1.5 interquartile range of the lower and upper quartile. Asterisks represent values outside the interquartile range. Dashed horizontal lines indicate serum free C5 concentration of 0.5 μg/mL.

cA Gyros-based fluorescence assay was used for patients who received ULTOMIRIS, and an electrochemiluminescence immunoassay was used for patients who received eculizumab. Baseline was defined as the last non-missing value before the first dose of study drug.

BL=baseline.

Pediatric study1,a

0%
of pediatric patients experienced
free C5 levels ≥0.5 μg/mL (n=0/13)

aThe pediatric study (ALXN1210-PNH-304; NCT03406507) was a 26-week, multicenter, open-label, phase 3 study. Pediatric patients (N=13) who were eculizumab-experienced (n=8) or complement inhibitor treatment-naïve (n=5) received ULTOMIRIS according to the recommended weight-based dosing regimen.

Pediatric patients

ULTOMIRIS is the only FDA-approved medication for pediatric patients one month of age and older with PNH.1

LEARN WHY

Physician resources

The Alexion OneSource team is ready to assist and support you and your patients.

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IMPORTANT SAFETY INFORMATION INCLUDING BOXED WARNING

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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.

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. In clinical studies, 59 adult patients with PNH were treated with ULTOMIRIS less than 2 weeks after meningococcal vaccination. All of these patients received antibiotics for prophylaxis of meningococcal infection until at least 2 weeks after meningococcal vaccination. The benefits and risks of antibiotic prophylaxis for prevention of meningococcal infections in patients receiving ULTOMIRIS have not been established. In PNH clinical studies in adult patients, 3 out of 261 PNH patients developed serious meningococcal infections/sepsis while receiving treatment with ULTOMIRIS; all 3 had been vaccinated. These 3 patients recovered while continuing treatment with ULTOMIRIS. 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
After discontinuing treatment with ULTOMIRIS, closely monitor for signs and symptoms of hemolysis, identified by elevated LDH along with sudden decrease in PNH clone size or hemoglobin, or re-appearance of symptoms such as fatigue, hemoglobinuria, abdominal pain, shortness of breath (dyspnea), major adverse vascular event (including thrombosis), dysphagia, or erectile dysfunction. Monitor any patient who discontinues ULTOMIRIS for at least 16 weeks to detect hemolysis and other reactions. If signs and symptoms of hemolysis occur after discontinuation, including elevated LDH, consider restarting treatment with ULTOMIRIS.

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, 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
Adverse reactions reported in 5% or more of patients treated with ULTOMIRIS vs. Eculizumab was Upper respiratory tract infection (39% vs. 39%), Headache (32% vs. 26%), Diarrhea (9% vs. 5%), Nausea (9% vs. 9%), Pyrexia (7% vs. 8%), Pain in extremity (6% vs. 5%), Abdominal pain (6% vs. 7%), Dizziness (5% vs. 6%), Arthralgia (5% vs. 5%). Serious adverse reactions were reported in 15 (6.8%) patients receiving ULTOMIRIS. The serious adverse reactions in patients treated with ULTOMIRIS included hyperthermia and pyrexia. No serious adverse reaction was reported in more than 1 patient treated with ULTOMIRIS. One fatal case of sepsis was identified in a patient treated with ULTOMIRIS.

Adverse reactions reported in 10% or more of pediatric patients treated with ULTOMIRIS who were treatment-naïve vs. Eculizumab-experienced was Anemia (20% vs. 25%), Abdominal pain (0% vs. 38%), Constipation (0% vs. 25%), Pyrexia (20% vs. 13%), Upper respiratory tract infection (20% vs. 75%), Pain in extremity (0% vs. 25%), Headache (20% vs. 25%).

INDICATION

ULTOMIRIS is indicated for the treatment of adult and pediatric patients one month of age and older with paroxysmal nocturnal hemoglobinuria (PNH).

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

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