SOLIRIS EFFICACY IN NMOSD

SOLIRIS® (eculizumab) significantly reduced the risk of relapse by 94% vs placebo in PREVENT

PREVENT

PREVENT OLE

Primary endpoint

The PREVENT study demonstrated that SOLIRIS is superior to placebo based on time to first adjudicated relapse (P<0.0001)1

94% reduction in risk of relapse
94% reduction in risk of relapse

The time to first adjudicated on-trial relapse was significantly longer in SOLIRIS-treated patients compared to patients on placebo (relative risk reduction, 94%; HR=0.058; 95% CI: 0.017, 0.197; P<0.0001).

Percentage of patients who were relapse-free infographic

Abbreviations: CI, confidence interval; HR, hazard ratio.

Kaplan-Meier plot shows time to first adjudicated relapse among patients receiving SOLIRIS or placebo for anti-AQP4 antibody-positive NMOSD in the analysis of the primary endpoint modified intent-to-treat population. Patients who did not experience an adjudicated on-trial relapse were censored at the end of the study period.1,2

Secondary endpoint

Significant relative reduction in on-trial adjudicated ARR1,2

Adjudicated ARR and Number of Adjudicated On-Trial Relapses with Soliris vs Placebo graph
Adjudicated ARR and Number of Adjudicated On-Trial Relapses with Soliris vs Placebo graph

SOLIRIS impact on relapse hospitalization and acute treatments

Compared to placebo, patients treated with SOLIRIS had reductions in annualized rates of1:

Soliris had reductions in annualized rates of compared to placebo
Soliris had reductions in annualized rates of compared to placebo

Abbreviation: IV, intravenous.

Additional prespecified analyses from the PREVENT study

Percentage of patients who were relapse-free at 96 and 144 weeks2

96 percent of patients were relapse-free at 96 weeks and 144 weeks
96 percent of patients were relapse-free at 96 weeks and 144 weeks

Study limitations: 96- and 144-week data

  • The time to first adjudicated on-trial relapse at weeks 96 and 144 was evaluated in a prespecified analysis2,3
  • The PREVENT study did not include enough patients beyond week 48 to determine whether a difference in time to the first adjudicated on-trial relapse between the 2 treatment groups at weeks 96 and 144 is statistically significant or clinically meaningful

Percentage of patients who were relapse-free on monotherapy2

100% of Soliris-treated patients were relapse free at 48 weeks
100% of Soliris-treated patients were relapse free at 48 weeks

Study limitations: monotherapy subgroup

  • The monotherapy subgroup analysis is exploratory, and it did not have enough patients to establish conclusions of benefit
  • During the treatment phase of the PREVENT study, 76% of patients (n=109) received concomitant immunosuppressive therapy, including chronic corticosteroids; 24% of patients (n=34) did not receive concomitant immunosuppressive therapy or chronic corticosteroids during the treatment phase of the study (monotherapy)1,2

PREVENT OLE study limitations

The primary goal of the PREVENT OLE was to evaluate the long-term safety of SOLIRIS in adult patients with anti-AQP4 antibody-positive NMOSD. To view these data, click here.

Please note any inference of efficacy or clinical significance should be interpreted with caution since the study was open-label and lacked a control group.

Secondary objective4

In PREVENT OLE, evaluation of the efficacy of SOLIRIS was a secondary objective

The primary efficacy endpoint was ARR based on the number of on-trial relapses identified by the treating physician and time in the study period.

On-Trial ARR (As Determined by the Treating Physician) Accounting for COVID-19 Disruption of Study Treatment – Extension Full Analysis Set

Variable Statistic Total
(N=119)
Historicala patient ARRb
Mean (SD)
Median
Min, max
2.013 (0.9932)
1.923
0.96, 6.38
Patient on-trial ARR in PREVENT OLEb
Mean (SD)
Median
Min, max
0.084 (0.3212)
0.000
0.00, 2.46
Change in ARR between historical ARR and PREVENT OLE on-trial ARR
Mean (SD)
Median
Min, max
95% CI for mean
-1.929 (1.0324)
-1.825
-6.38, 1.02
(-2.116, -1.741)

For patients who missed 2 or more doses consecutively due to COVID-19–related reasons, the time period for the calculation of PREVENT OLE on-trial ARR excludes the time period when the patient missed SOLIRIS infusion to account for the impact of the pandemic. Any relapse occurring during this period was not included in the calculation of PREVENT OLE on-trial ARR.
aBased on 24 months prior to screening in PREVENT study.
bThe number of relapses for each patient divided by the number of years in the study period for that patient; summary statistics across all patients are presented.
Abbreviation: COVID-19, coronavirus disease of 2019.

Primary Analysis: Kaplan-Meier Survival Estimates for Time to First On-Trial Relapse (As Determined by the Treating Physician) in PREVENT OLE Censored for COVID-19 Disruption of Study Treatment

Percentage of patients who were relapse-free infographic

Note: Patients who did not experience an on-trial relapse as determined by the treating physician were censored at the end of the study period.

For patients who missed 2 or more doses consecutively due to COVID-19–related reasons, the study period was truncated to the last dose date prior to missing 2 or more infusions consecutively due to COVID-19–related reasons + 16 days (or + 9 days if in induction phase), and patients who did not experience an on-trial relapse were censored at this date. Estimated proportion of patients relapse-free was only presented when the number of patients at risk in the total group at the time point was at least 5.

aBased on the Kaplan-Meier product limit method.
bBased on the complementary log-log transformation.

One hundred six (89.1%) patients in the PREVENT OLE did not experience an on-trial relapse during the study. Of the 13 patients who experienced an on-trial relapse (as determined by the treating physician), 9 patients had 1 relapse, 1 patient had 2 relapses, and 3 patients had 3 relapses.

An additional 2 patients each experienced 1 on-trial relapse as determined by the treating physician during a dose interruption due to COVID-19; both of these relapses were adjudicated positively. Sensitivity analyses, including these 2 relapses, were consistent with those of the primary analyses, which accounted for COVID-19 disruption of study treatment.

Sensitivity Analysis: Kaplan-Meier Survival Estimates for Time to First Adjudicated On-Trial Relapse in PREVENT OLE Censored for COVID-19 Disruption of Study Treatment

Percentage of patients who were relapse-free infographic

Note: Patients who did not experience an adjudicated on-trial relapse were censored at the end of the study period.

For patients who missed 2 or more doses consecutively due to COVID-19–related reasons, the study period was truncated to the last dose date prior to missing 2 or more doses consecutively due to COVID-19–related reasons + 16 days (or + 9 days if in induction phase), and patients who did not experience an adjudicated on-trial relapse were censored at this date. Estimated proportion of relapse-free patients was only presented when the number of patients at risk in the total group at a time point was at least 5.

aBased on the Kaplan-Meier product limit method.
bBased on the complementary log-log transformation.

One hundred thirteen (95.0%) patients in PREVENT OLE did not experience an adjudicated on-trial relapse during the study. Of the 6 patients who experienced an adjudicated on-trial relapse, 5 had 1 adjudicated relapse and 1 had 2 adjudicated relapses.

An additional 2 patients each experienced 1 on-trial relapse as determined by the treating physician during a dose interruption due to COVID-19; both of these relapses were adjudicated positively. Sensitivity analyses, including these 2 relapses, were consistent with those of the primary analyses, which accounted for COVID-19 disruption of study treatment. These 2 relapses are not reflected in this Kaplan-Meier Survival Estimate figure.

NEXT Safety

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IMPORTANT SAFETY INFORMATION & INDICATION FOR SOLIRIS® (eculizumab), INCLUDING BOXED WARNING

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WARNING: SERIOUS MENINGOCOCCAL INFECTIONS

SOLIRIS, 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 SOLIRIS, unless the risks of delaying SOLIRIS 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 SOLIRIS 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, SOLIRIS 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
  • SOLIRIS is contraindicated for initiation in patients with unresolved serious Neisseria meningitidis infection.
WARNINGS AND PRECAUTIONS
Serious Meningococcal Infections

SOLIRIS, 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 therapy with SOLIRIS. 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 SOLIRIS therapy is indicated in a patient who is not up to date with meningococcal vaccines according to ACIP recommendations, provide the patient with 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 SOLIRIS. The benefits and risks of treatment with SOLIRIS, 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 these signs and symptoms occur. Promptly treat known infections. Meningococcal infection may become rapidly life-threatening or fatal if not recognized and treated early. Consider interruption of SOLIRIS 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, SOLIRIS 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 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 SOLIRIS. 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 SOLIRIS. Patients must receive counseling about the need to receive meningococcal vaccines and to take antibiotics as directed, the signs and symptoms of meningococcal infection, and be instructed to carry the Patient Safety Card with them at all times during and for 3 months following SOLIRIS 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.

SOLIRIS blocks terminal complement activation; therefore, patients may have increased susceptibility to infections, especially with encapsulated bacteria, such as infections with Neisseria meningitidis but also Streptococcus pneumoniae, Haemophilus influenzae, and to a lesser extent, Neisseria gonorrhoeae. Additionally, Aspergillus infections have occurred in immunocompromised and neutropenic patients. Patients receiving SOLIRIS are at increased risk for infections due to these organisms, even if they develop antibodies following vaccination.

Thrombosis Prevention and Management

The effect of withdrawal of anticoagulant therapy during SOLIRIS treatment has not been established. Therefore, treatment with SOLIRIS should not alter anticoagulant management.

Infusion-Related Reactions

Administration of SOLIRIS may result in infusion-related reactions, including anaphylaxis or other hypersensitivity reactions. In clinical trials, no patients experienced an infusion-related reaction which required discontinuation of SOLIRIS. Interrupt SOLIRIS infusion and institute appropriate supportive measures if signs of cardiovascular instability or respiratory compromise occur. 

ADVERSE REACTIONS

The most frequently reported adverse reactions in the NMOSD placebo-controlled trial (≥10%) were: upper respiratory infection, nasopharyngitis, diarrhea, back pain, dizziness, influenza, arthralgia, pharyngitis, and contusion.

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.

INDICATION

SOLIRIS is indicated for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adult patients who are anti-aquaporin-4 (AQP4) antibody positive.

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

IMPORTANT SAFETY INFORMATION & INDICATION FOR SOLIRIS® (eculizumab), INCLUDING BOXED WARNING
WARNING: SERIOUS MENINGOCOCCAL INFECTIONS

SOLIRIS, 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 SOLIRIS, unless the risks of delaying SOLIRIS 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 SOLIRIS 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, SOLIRIS 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
  • SOLIRIS is contraindicated for initiation in patients with unresolved serious Neisseria meningitidis infection.
WARNINGS AND PRECAUTIONS
Serious Meningococcal Infections

SOLIRIS, 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 therapy with SOLIRIS. 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 SOLIRIS therapy is indicated in a patient who is not up to date with meningococcal vaccines according to ACIP recommendations, provide the patient with 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 SOLIRIS. The benefits and risks of treatment with SOLIRIS, 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 these signs and symptoms occur. Promptly treat known infections. Meningococcal infection may become rapidly life-threatening or fatal if not recognized and treated early. Consider interruption of SOLIRIS 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, SOLIRIS 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 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 SOLIRIS. 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 SOLIRIS. Patients must receive counseling about the need to receive meningococcal vaccines and to take antibiotics as directed, the signs and symptoms of meningococcal infection, and be instructed to carry the Patient Safety Card with them at all times during and for 3 months following SOLIRIS 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.

SOLIRIS blocks terminal complement activation; therefore, patients may have increased susceptibility to infections, especially with encapsulated bacteria, such as infections with Neisseria meningitidis but also Streptococcus pneumoniae, Haemophilus influenzae, and to a lesser extent, Neisseria gonorrhoeae. Additionally, Aspergillus infections have occurred in immunocompromised and neutropenic patients. Patients receiving SOLIRIS are at increased risk for infections due to these organisms, even if they develop antibodies following vaccination.

Thrombosis Prevention and Management

The effect of withdrawal of anticoagulant therapy during SOLIRIS treatment has not been established. Therefore, treatment with SOLIRIS should not alter anticoagulant management.

Infusion-Related Reactions

Administration of SOLIRIS may result in infusion-related reactions, including anaphylaxis or other hypersensitivity reactions. In clinical trials, no patients experienced an infusion-related reaction which required discontinuation of SOLIRIS. Interrupt SOLIRIS infusion and institute appropriate supportive measures if signs of cardiovascular instability or respiratory compromise occur. 

ADVERSE REACTIONS

The most frequently reported adverse reactions in the NMOSD placebo-controlled trial (≥10%) were: upper respiratory infection, nasopharyngitis, diarrhea, back pain, dizziness, influenza, arthralgia, pharyngitis, and contusion.

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.

INDICATION

SOLIRIS is indicated for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adult patients who are anti-aquaporin-4 (AQP4) antibody positive.

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

References
1. SOLIRIS. Prescribing information. Alexion Pharmaceuticals, Inc. 2. Pittock SJ, Berthele A, Fujihara K, et al. Eculizumab in aquaporin-4-positive neuromyelitis optica spectrum disorder. N Engl J Med. 2019;381(7):614-625. doi:10.1056/NEJMoa1900866 3. Pittock SJ, Berthele A, Fujihara K, et al. Eculizumab in aquaporin-4-positive neuromyelitis optica spectrum disorder. N Engl J Med. 2019;381(7)(suppl 1-36):614-625. doi:10.1186/1742-2094-9-14 4. Data on file. Alexion Pharmaceuticals, Inc.

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