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NOW FDA APPROVED
ULTOMIRIS (ravulizumab-cwvz) is the FIRST and ONLY terminal complement inhibitor approved for adults with primary IgAN1
ULTOMIRIS is indicated to reduce proteinuria in adults with primary immunoglobulin A nephropathy (IgAN) at risk for disease progression. This indication is approved under accelerated approval based on reduction of proteinuria. It has not been established whether ULTOMIRIS slows kidney function decline in patients with IgAN. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory clinical trial.
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The FIRST and ONLY terminal complement inhibitor approved for adults with primary IgAN1
ULTOMIRIS specifically binds to complement protein C5 to inhibit terminal complement activity.1
In IgAN, the deposition of galactose deficient IgA1 (Gd-IgA) containing immune complexes in the kidney locally activates the alternative and/or lectin complement pathways which are thought to contribute to the pathogenesis of IgAN. By blocking C5, ULTOMIRIS inhibits terminal complement activation.1
C5, complement protein C5; IgAN, immunoglobulin A nephropathy; IgA1, immunoglobulin A1.
EFFICACY
Significant reductions in proteinuria at 34 weeks1
STUDY DESIGN
I CAN: A Phase 3 Study in IgAN

The efficacy and safety of ULTOMIRIS were evaluated in the randomized, double-blind, placebo-controlled, Phase 3 study.1

The main cohort of the I CAN study included 485 adults with biopsy-proven IgAN, eGFR ≥30 mL/min/1.73 m², and urine protein creatinine ratio (UPCR) ≥0.75 g/g or urine protein ≥1 g/day receiving a stable dose of maximally tolerated renin-angiotensin-aldosterone system inhibitor (RAASi) therapy, with or without other stable concomitant IgAN therapy (SGLT2i, DEARA, MRA, or ERA).1*

  • Patients were required to receive meningococcal vaccination or antibacterial prophylaxis consistent with study requirements1
  • Patients with other glomerulopathies or recent systemic immunosuppressant treatment were excluded1

*The study also enrolled an exploratory advanced kidney disease cohort (eGFR ≥20 and ≤29 mL/min/1.73 m²).

Primary Endpoint

  • Percent reduction from baseline in 24-hour UPCR at Week 34 relative to baseline
  • Efficacy analysis was based on 352 patients who had the opportunity to complete Week 34 prior to the interim data cut

Baseline Patient Characteristics1

  • Age, mean: 43 years (range: 18 years-76 years)
  • Sex, male: 58%
  • Race: 36% White, 58% Asian
  • eGFR, mean: 65 mL/min/1.73 m²
  • UPCR, mean (from two 24-hour urine collections): 1.9 g/g
  • SGLT2i use: 69%
  • Hypertension: 59%
  • Hematuria: 80%

Patients were randomized 1:1 to receive ULTOMIRIS (n=176) or placebo (n=176).

DEARA, dual endothelin angiotensin receptor antagonist; eGFR, estimated glomerular filtration rate; ERA, endothelin receptor antagonist; IgAN, immunoglobulin A nephropathy; MRA, mineralocorticoid receptor antagonist; SGLT2i, sodium-glucose cotransporter 2 inhibitor.
The efficacy and safety of ULTOMIRIS were evaluated in the randomized, double-blind, placebo-controlled, Phase 3 study.1 The main cohort of the I CAN study included 485 adults with biopsy-proven IgAN, eGFR ≥30 mL/min/1.73 m², and urine protein creatinine ratio (UPCR) ≥0.75 g/g or urine protein ≥1 g/day on a stable dose of maximally tolerated RAASi therapy with or without other concomitant IgAN therapy (SGLT2 inhibitor, DEARA, MRA, or ERA).
  • ULTOMIRIS reduced 24-hour UPCR* levels by 47% from baseline to Week 34, compared with a 6% reduction with placebo—a placebo-adjusted treatment effect of 43% (95% CI: 34%, 52%; P<0.0001)1

  • Decreases in 24-hour UPCR were observed as early as Week 101
Percent Change From Baseline in 24-Hour UPCR* by Visit1
*Percent reduction in UPCR was obtained from the adjusted geometric mean ratios from an MMRM analyzing log-transformed UPCR.1
Treatment with ULTOMIRIS reduced proteinuria consistently across subgroups in the main cohort (including race, regions, baseline eGFR, age, sex, baseline proteinuria levels, and the use of SGLT2i).1
CI, confidence interval; DEARA, dual endothelin angiotensin receptor antagonist; eGFR, estimated glomerular filtration rate; ERA, endothelin receptor antagonist; IgAN, immunoglobulin A nephropathy; MMRM, mixed-effects model repeated measures; MRA, mineralocorticoid receptor antagonist; SGLT2, sodium-glucose cotransporter 2.
SAFETY
The ULTOMIRIS safety profile
In the Phase 3 study, the most frequent adverse reaction (≥10%) with ULTOMIRIS was upper respiratory tract infection.1 Serious adverse reactions were reported in 11 (4.6%) patients receiving ULTOMIRIS and in 22 (9.0%) patients receiving placebo.
Adverse Reactions Reported in ≥5% and at Greater Frequency Than Placebo in ULTOMIRIS-Treated Adult Patients With IgAN in the I CAN Study1
ULTOMIRIS 100 mg/mL dosing overview
ULTOMIRIS provides adult patients with intravenous (IV) infusions with once-every-8-week maintenance dosing, starting 2 weeks after an initial loading dose.1
The recommended IV ULTOMIRIS loading and maintenance dosing in adult patients with IgAN weighing 40 kg or greater is based on the patient’s body weight, with maintenance doses administered every 8 weeks, starting 2 weeks after the loading dose.1
IV Administration of ULTOMIRIS Weight-Based Dosing for IgAN1

The IV dosing schedule is allowed to occasionally vary within 7 days of the scheduled infusion day (except for the first maintenance dose of ULTOMIRIS); but subsequent doses should be administered according to the original schedule.1

Following a missed IV ULTOMIRIS dose, the patient should contact their healthcare provider immediately.1
IgAN, immunoglobulin A nephropathy
Enroll in the REMS program called ULTOMIRIS and SOLIRIS REMS

Due to the risk of meningococcal infections, ULTOMIRIS is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS). Under the REMS program, prescribers must enroll in the program. Healthcare settings and pharmacies that dispense ULTOMIRIS must be certified in the REMS and must verify prescribers are certified.


Prescribers must counsel patients about the risk of meningococcal infection/sepsis, provide the patients with the REMS educational materials, and assess vaccination status for meningococcal vaccines. Patients must be instructed to carry the Patient Safety Card with them at all times during and for 8 months following treatment with ULTOMIRIS.


Enrollment in the REMS program and additional information are available at 1-888-765-4747 or online.

 Vaccinate to reduce infection risk

Vaccinate and revaccinate patients 2 weeks prior to the first dose of ULTOMIRIS in accordance with the Advisory Committee on Immunization Practices (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.1


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.1


Vaccination does not eliminate the risk of serious meningococcal infections, despite development of antibodies following vaccination.1

 
To start your patient on ULTOMIRIS, download the Start Form.
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ULTOMIRIS. Prescribing Information. Alexion Pharmaceuticals, Inc.

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

Prescribers must enroll in the REMS, counsel patients about the risk of serious 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.UltSolREMS.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. Patients receiving ULTOMIRIS are at increased risk for infections due to these organisms, even if they develop antibodies following vaccination.

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 systemic infusion-related reactions, including anaphylaxis and hypersensitivity reactions. In clinical trials, infusion-related reactions occurred in approximately 1 to 8% of patients, including lower back pain, abdominal pain, muscle spasms, drop or elevation in blood pressure, rigors, limb discomfort, drug hypersensitivity (allergic reaction), and dysgeusia (bad taste). These reactions did not require discontinuation of ULTOMIRIS. If signs of cardiovascular instability or respiratory compromise occur, interrupt ULTOMIRIS and institute appropriate supportive measures.

ADVERSE REACTIONS
Most common adverse reaction in adult patients with IgAN (incidence ≥ 10%) was upper respiratory tract infection. Serious adverse reactions were reported in 11 (4.6%) patients with IgAN receiving ULTOMIRIS and in 22 (9.0%) patients receiving placebo.

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.

Use in Specific Populations
Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ULTOMIRIS during pregnancy. Healthcare providers and patients may call 1-833-793-0563 or go to www.UltomirisPregnancyStudy.com to enroll in or to obtain information about the registry.

To report SUSPECTED ADVERSE REACTIONS, contact Alexion Pharmaceuticals, Inc. at 11-844-259-6783 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Indication
ULTOMIRIS is indicated to reduce proteinuria in adults with primary immunoglobulin A nephropathy (IgAN) at risk for disease progression.

This indication is approved under accelerated approval based on reduction of proteinuria. It has not been established whether ULTOMIRIS slows kidney function decline in patients with IgAN. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory clinical trial.

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