In the 2-year AFFIRM pivotal trial:

Relapsing MS patients received 300 mg TYSABRI every 28 days (n=627) or placebo (n=315). Patients with PPMS, SPMS, and PRMS were excluded.

83% of patients taking TYSABRI had no sustained disability progression for 12 weeks vs 71% with placebo (primary endpoint: 17% vs 29%; p<0.001)1,2

TYSABRI demonstrated 67% relative reduction in ARR vs placebo (secondary endpoint: 0.22 vs 0.67; p<0.001)1,2

LONG-TERM OBSERVATIONAL STUDY OF OVER 6000 PATIENTS REAFFIRMS THE TYSABRI SAFETY PROFILE.3

Study description: TOP is an ongoing, open-label, multinational, multicenter, prospective study observing 6148 patients with RRMS outside of the US receiving 300 mg TYSABRI IV every 4 weeks for 15 years in real-world clinical practice settings. Of the 6148 patients enrolled, 3210 patients have discontinued TYSABRI, and 2117 have withdrawn from TOP. Of the 3210 patients who have discontinued TYSABRI treatment, 1093 remain in TOP. RRMS patients enrolled in TOP are required to be TYSABRI-naïve or to have received ≤3 doses of TYSABRI in their lifetime. This 10-year interim analysis includes data from study initiation (July 2007) through November 1, 2017. 

Study limitations3:

  • The study is ongoing and observational, without randomization or a placebo control group
  • Attrition bias in inherent in long-term observational studies. Analysis of attrition bias is limited by the small number of patients in the <8-year treatment group, which decreased from 1056 at baseline to 389 at 8 years. The decrease occurred at various time points, resulting in varied treatment durations
  • Results should be interpreted with caution, as treatment practices vary by country

The longest evaluation of real-world outcomes in patients treated with TYSABRI to date

  • In 2007, Biogen initiated TOP, which assessed real-world safety and efficacy outcomes in patients treated with TYSABRI across the globe and is planned to continue out to 15 years
See AFFIRM pivotal trial data for context
 
Explore the well-understood safety profile of TYSABRI
 

>85% of patients receiving TYSABRI experienced no SAEs in the 10-year TOP study

INCIDENCE OF SAEs OCCURRING IN ≥10 PATIENTS IN TOP

MedDRA PREFERRED TERM N=6148, n (%)a
Immune reconstitution inflammatory syndrome (IRIS)b 54 (0.9)
Progressive multifocal leukoencephalopathy (PML), confirmed 53 (0.9)
Abortion spontaneous 37 (0.6)
Hypersensitivity 26 (0.4)
Pneumonia 23 (0.4)
Urinary tract infection 20 (0.3)
Fall 19 (0.3)
Depression 18 (0.3)
Epilepsy 18 (0.3)
Herpes zoster 17 (0.3)
Breast cancer 12 (0.2)
Intervertebral disc protrusion 12 (0.2)
Escherichia urinary tract infection 12 (0.2)
Suicide attempt 11 (0.2)
Pulmonary embolism 10 (0.2)
Pyelonephritis 10 (0.2)

Copyright © 2020 Butzkueven H, et al; licensee BMJ is adapted under CC BY-NC.

aEach patient was counted only once within each preferred term. Multiple sclerosis relapse was also reported as an SAE in 20 patients (0.3%).3

bOne case of immune reconstitution inflammatory syndrome was not associated with PML.3

  • SAEs related to hypersensitivity reactions (n=40, <0.7% of patients) included anaphylactic reaction (n=4), anaphylactoid reaction (n=3), anaphylactic shock (n=5), and hypersensitivity (n=28)
  • 12 hepatic events (<0.2% of patients) were reported during the study
  • 30 deaths (<0.5%) were reported during the study
    • Physicians classified 8 deaths as treatment related, which included PML (n=4), IRIS (n=2, one of which was combined with MS relapse), metastatic breast cancer (n=1), and autonomic nervous system imbalance (n=1)

Incidence rates for opportunistic infections, malignancy, and PML were low (~1%)

SERIOUS ADVERSE EVENTS OF INTEREST

OVERALL
EXPOSURE
(26,060 patient-yearsc; N=6148)		 FIRST 3 YEARS
ON TREATMENT
(15,773 patient-yearsc; N=6148)		 BEYOND 3 YEARS
ON TREATMENT
(10,233 patient-yearsc; N=3719)
Patients with event, n (%) Incidence rate
(95% CI)d,e
Patients with event, n (%) Incidence rate
(95% CI)d,e
Patients with event, n (%) Incidence rate
(95% CI)d,e
Opportunistic infections other than PML
11 (0.18) 0.422
(0.234-0.762)
10 (0.16) 0.634
(0.341-1.178)
1 (0.03) 0.098
(0.014-0.694)
PML, confirmed
53 (0.86) 2.034
(1.554-2.662)
17 (0.28) 1.078
(0.67-1.734)
36 (0.97) 3.518
(2.537-4.877)
Malignancy
63 (1.02) 2.417
(1.889-3.095)
35 (0.57) 2.219
(1.593-3.090)
28 (0.75) 2.736
(1.889-3.963)
OVERALL EXPOSURE
(26,060 patient-yearsc; N=6148)
Patients with event, n% Incidence rate (95% CI)d,e
Opportunistic infections other than PML 11 (0.18) 0.422
(0.234-0.762)
PML, confirmed 53 (0.86) 2.034
(1.554-2.662)
Malignancy 63 (1.02) 2.417
(1.889-3.095)
FIRST 3 YEARS ON TREATMENT
(15,773 patient-yearsc; N=6148)
Patients with event, n% Incidence rate (95% CI)d,e
Opportunistic infections other than PML 10 (0.16) 0.634
(0.341-1.178)
PML, confirmed 17 (0.28) 1.078
(0.67-1.734)
Malignancy 35 (0.57) 2.219
(1.593-3.090)
BEYOND 3 YEARS ON TREATMENT
(10,233 patient-yearsc; N=3719)
Patients with event, n% Incidence rate (95% CI)d,e
Opportunistic infections other than PML 1 (0.03) 0.098
(0.014-0.694)
PML, confirmed 36 (0.97) 3.518
(2.537-4.877)
Malignancy 28 (0.75) 2.736
(1.889-3.963)

Copyright © 2020 Butzkueven H, et al; licensee BMJ is adapted under CC BY-NC.

cBased on the time from the first dose of natalizumab until the last natalizumab dosing date + 6 months.3

dCalculated as (1000 × number of patients with an event) / (total patient-years of follow-up).3

eExact CIs are calculated based on the Poisson distribution.3

  • Results are in line with the current understanding of the risk factors for PML
    • Prior immunosuppressant use was reported by 26.4% of patients with PML 
    • 97.2% of PML cases (35 out of 36) with reported anti-JCV antibody serostatus 6 months prior to PML development were confirmed positive
    • JCV status was not tested at enrollment in 1809 out of 6148 patients (29.4%) and was missing from 7 patients who were tested at enrollment (0.1%)
    • 67.9% of PML cases (36 out of 53) occurred in patients receiving natalizumab for >3 years
  • Overall, there were 66 patients with 39 types of malignancies
  • Incidence of breast cancer was 0.3% (19 of 6148 patients), or 86.7 per 100,000 patient-years with TYSABRI (95% CI: 52.2-135.4 per 100,000 patient-years)
See 10-Year Efficacy Data

Results are consistent with the current understanding of PML risk factors

TYSABRI had a sustained impact on disability progression and ARR out to 10 years3,f

Copyright © 2020 Butzkueven H, et al; licensee BMJ is adapted under CC BY-NC.

fCumulative probability of confirmed disability worsening was defined as an increase of ≥1.5 from a baseline score of 0.0, ≥1.0 from a score of 1.0-5.5, or ≥0.5 from a score of ≥6.0, sustained for 24 weeks.3

Median EDSS scores were stable over 10 years

MEDIAN EDSS SCORES IN THE OVERALL STUDY POPULATION FROM ENROLLMENT TO YEAR 10
Year 0
(n=6088)
Year 1
(n=5696)
Year 2
(n=4995)
Year 3
(n=4359)
Year 4
(n=3808)
Year 5
(n=3156)
Year 6
(n=2395)
Year 7
(n=1771)
Year 8
(n=1126)
Year 9
(n=533)
Year 10
(n=208)
Median
EDSS score
3.5
3.0
3.0
3.0
3.0
3.0
3.5
3.5
3.5
4.0
4.0
MEDIAN EDSS SCORES IN THE OVERALL
STUDY POPULATION FROM
ENROLLMENT TO YEAR 10
Median EDSS score
Year 0 (n=6088) 3.5
Year 1 (n=5696) 3.0
Year 2 (n=4995) 3.0
Year 3 (n=4359) 3.0
Year 4 (n=3808) 3.0
Year 5 (n=3156) 3.0
Year 6 (n=2395) 3.5
Year 7 (n=1771) 3.5
Year 8 (n=1126) 3.5
Year 9 (n=533) 4.0
Year 10 (n=208) 4.0
  • At Year 10, very few patients were eligible to be counted due to disability progression measurements (which had to verify sustained progression 6 months after detecting progression), low initial enrollment, and treatment discontinuations

TYSABRI reduced relapses by 88% at Year 1, with low ARRs (≤0.21) sustained out to 10 years3,g

Copyright © 2020 Butzkueven H, et al; licensee BMJ is adapted under CC BY-NC.

gARRs for the year prior to starting natalizumab and the period during which patients were on natalizumab (and ≤84 days after the last dose) were compared using a repeated Poisson model.3

TYSABRI administration early in the treatment course reduced relapses by 88% at Year 1, with low ARR sustained out to 10 years.

  • In the overall population, ARR decreased from 1.99 at baseline to 0.24 after 1 year of TYSABRI treatment, and ARRs remained ≤0.20 out to 10 years. Similar results were observed in the other cohorts:
    • In the ≥8-year treatment cohort, ARR decreased from 2.04 at baseline to 0.21 at Year 1, and ARRs remained ≤0.21 in subsequent years
    • In the <8-year treatment cohort, ARR decreased from 1.97 at baseline to 0.26 at Year 1, and ARRs remained ≤0.21 in subsequent years

ARR decreased by >90% for patients taking TYSABRI, regardless of baseline EDSS3

ARR BY BASELINE EDSS

  • Patients experienced lower ARR when TYSABRI was used at lower baseline EDSS scores (≤3.0)
  • Patients achieved a significant reduction in clinical disease activity, as defined by ARR, regardless of high EDSS scores (≥3.0)

Early use of TYSABRI in patients resulted in a lower ARR than did later use of TYSABRI3

ARR BY NUMBER OF PRIOR DMTs

  • Patients experienced lower ARR when TYSABRI was used earlier in the treatment course (for patients with no prior DMT use vs those who had taken ≥2 prior DMTs)
  • Patients achieved a significant reduction in clinical disease activity, as defined by ARR, regardless of prior use of DMTs (≥1)

ARR was lower in patients who received TYSABRI after ≤1 relapse in the prior year vs >1 relapse3

ARR BY PRIOR RELAPSES

  • Patients experienced lower ARR when TYSABRI was used at lower pre-TYSABRI relapse rates (≤1 relapse in prior year)
  • Patients achieved a significant reduction in clinical disease activity, as defined by ARR, regardless of a higher number of relapses (>1 in prior year)

TYSABRI reduced ARR in the 10-year TOP study when used early
or late in the disease course3

See 10-Year Safety Data
NEXT:
Global Safety Study

The TOP Study was funded by Biogen.

INDICATION

TYSABRI® (natalizumab) is indicated as monotherapy for the treatment of relapsing forms of multiple sclerosis, to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults. TYSABRI increases the risk of PML. When initiating and continuing treatment with TYSABRI, physicians should consider whether the expected benefit of TYSABRI is sufficient to offset this risk.

IMPORTANT SAFETY INFORMATION

WARNING: Progressive Multifocal Leukoencephalopathy (PML)

TYSABRI® (natalizumab) increases the risk of PML, an opportunistic viral infection of the brain that usually leads to death or severe disability. Risk factors for the development of PML include the presence of anti-JCV antibodies, duration of therapy, and prior use of immunosuppressants. These factors should be considered in the context of expected benefit when initiating and continuing treatment with TYSABRI.

Healthcare professionals should monitor patients on TYSABRI for any new sign or symptom that may be suggestive of PML. TYSABRI dosing should be withheld immediately at the first sign or symptom suggestive of PML. For diagnosis, an evaluation including a gadolinium-enhanced MRI scan of the brain and, when indicated, cerebrospinal fluid analysis for JC viral DNA are recommended.

Because of the risk of PML, TYSABRI is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the TOUCH® Prescribing Program.

  • Infection by the JC Virus (JCV) is required for the development of PML
  • There are no known interventions that can reliably prevent PML or that can adequately treat PML if it occurs
  • Postmarketing data suggest that the risk of developing PML may be associated with relative levels of serum anti-JCV antibody compared to a calibrator as measured by ELISA (often described as an anti-JCV antibody index value)
  • MRI findings may be apparent before clinical signs or symptoms suggestive of PML. Monitoring with MRI for signs that may be consistent with PML may be useful, and any suspicious findings should lead to further investigation to allow for an early diagnosis of PML, if present. Consider monitoring patients at high risk for PML more frequently. Lower PML-related mortality and morbidity have been reported following TYSABRI discontinuation in patients with PML who were initially asymptomatic compared to patients with PML who had characteristic clinical signs and symptoms at diagnosis
  • PML has been reported after discontinuation of TYSABRI in patients who did not have findings suggestive of PML at the time of discontinuation. Patients should continue to be monitored for any new signs or symptoms that may be suggestive of PML for at least 6 months after discontinuation of TYSABRI
  • Adverse events that may occur during plasma exchange (PLEX) include clearance of other medications and volume shifts, which have the potential to lead to hypotension or pulmonary edema. Although PLEX has not been prospectively studied in TYSABRI-treated patients with PML, it has been used in such patients in the postmarketing setting to remove TYSABRI more quickly from the circulation. There is no evidence that PLEX has any benefit in the treatment of opportunistic infections such as PML
  • JCV infection of granule cell neurons in the cerebellum, i.e., JCV granule cell neuronopathy (GCN), with symptoms similar to PML, has been reported in patients treated with TYSABRI. JCV GCN can occur with or without concomitant PML and can cause cerebellar dysfunction. Diagnosis and management of JCV GCN should follow guidance provided for PML
  • Immune reconstitution inflammatory syndrome (IRIS) has been reported in the majority of TYSABRI-treated patients who developed PML and subsequently discontinued TYSABRI. In almost all cases, IRIS occurred after PLEX was used to eliminate circulating TYSABRI. It presents as a clinical decline in the patient’s condition after TYSABRI removal (and, in some cases, after apparent clinical improvement) that may be rapid, can lead to serious neurological complications or death, and is often associated with characteristic changes in the MRI. TYSABRI has not been associated with IRIS in patients discontinuing treatment with TYSABRI for reasons unrelated to PML. In TYSABRI-treated patients with PML, IRIS has been reported within days to several weeks after PLEX. Monitoring for development of IRIS and appropriate treatment of the associated inflammation should be undertaken

Contraindications

  • TYSABRI is contraindicated in patients who have or have had PML
  • TYSABRI is contraindicated in patients who have had a hypersensitivity reaction to TYSABRI

TYSABRI TOUCH Prescribing Program

  • Because of the risk of PML, TYSABRI is available only through a restricted distribution program under a REMS called the TOUCH® Prescribing Program
  • Patients must be enrolled in the TOUCH Prescribing Program, read the Medication Guide, understand the risks associated with TYSABRI, and complete and sign the Patient-Prescriber Enrollment Form

Herpes Infections – Encephalitis, Meningitis and Acute Retinal Necrosis

  • TYSABRI increases the risk of developing encephalitis and meningitis caused by herpes simplex and varicella zoster viruses
  • Serious, life-threatening, and sometimes fatal cases have been reported in the postmarketing setting in multiple sclerosis patients receiving TYSABRI
  • The duration of treatment with TYSABRI prior to onset ranged from a few months to several years
  • Monitor patients receiving TYSABRI for signs and symptoms of meningitis and encephalitis. If herpes encephalitis or meningitis occurs, TYSABRI should be discontinued, and appropriate treatment for herpes encephalitis/meningitis should be administered
  • Patients being administered TYSABRI are at a higher risk of acute retinal necrosis (ARN), a fulminant viral infection of the retina caused by the family of herpes viruses. Patients with eye symptoms such as decreased visual acuity, redness or eye pain should be referred for retinal screening as serious cases of ARN can lead to blindness of one or both eyes
  • Following clinical diagnosis of ARN, consider discontinuation of TYSABRI

Hepatotoxicity

  • Clinically significant liver injury, including acute liver failure requiring transplant, has been reported in patients treated with TYSABRI in the postmarketing setting
  • Signs of liver injury, including markedly elevated serum hepatic enzymes and elevated total bilirubin, occurred as early as six days after the first dose; signs of liver injury have also been reported for the first time after multiple doses
  • TYSABRI should be discontinued in patients with jaundice or other evidence of significant liver injury (e.g., laboratory evidence)

Hypersensitivity/Antibody Formation

  • Hypersensitivity reactions have occurred in patients receiving TYSABRI, including serious systemic reactions (e.g., anaphylaxis) which occurred at an incidence of <1%
  • Reactions usually occur within 2 hours of the start of the infusion. Symptoms associated with these reactions can include urticaria, dizziness, fever, rash, rigors, pruritus, nausea, flushing, hypotension, dyspnea, and chest pain
  • If a hypersensitivity reaction occurs, discontinue administration of TYSABRI and initiate appropriate therapy. Patients who experience a hypersensitivity reaction should not be re-treated with TYSABRI
  • Hypersensitivity reactions were more frequent in patients with antibodies to TYSABRI compared with patients who did not develop antibodies to TYSABRI in both MS and CD studies
  • Patients who receive TYSABRI for a short exposure (1 to 2 infusions) followed by an extended period without treatment are at higher risk of developing anti-natalizumab antibodies and/or hypersensitivity reactions on re-exposure, compared to patients who received regularly scheduled treatment

Immunosuppression/Infections

  • The immune system effects of TYSABRI may increase the risk for infections
  • In Study MS1, certain types of infections—including pneumonias and urinary tract infections (including serious cases), gastroenteritis, vaginal infections, tooth infections, tonsillitis, and herpes infections—occurred more often in TYSABRI-treated patients than in placebo-treated patients. One opportunistic infection, a cryptosporidial gastroenteritis with a prolonged course, was observed in a patient who received TYSABRI in Study MS1
  • In Studies MS1 and MS2, an increase in infections was seen in patients concurrently receiving short courses of corticosteroids. However, the increase in infections in TYSABRI-treated patients who received steroids was similar to the increase in placebo-treated patients who received steroids
  • In a long-term safety study of patients, opportunistic infections (pulmonary mycobacterium avium intracellulare, aspergilloma, cryptococcal fungemia and meningitis, and Candida pneumonia) have been observed in <1% of TYSABRI-treated patients
  • Concurrent use of antineoplastic, immunosuppressant, or immunomodulating agents may further increase the risk of infections over the risk observed with use of TYSABRI alone
  • In Studies MS1 and MS2, the rate of any type of infection was approximately 1.5 per patient-year in both TYSABRI-treated patients and placebo-treated patients
  • In Study MS1, the incidence of serious infections was approximately 3% in TYSABRI-treated patients and in placebo-treated patients. Most patients did not interrupt treatment with TYSABRI during infections

Laboratory Test Abnormalities

  • In clinical trials, TYSABRI was observed to induce increases in circulating lymphocytes, monocytes, eosinophils, basophils, and nucleated red blood cells. Observed changes persisted during TYSABRI exposure, but were reversible, returning to baseline levels usually within 16 weeks after the last dose. Elevations of neutrophils were not observed. TYSABRI induces mild decreases in hemoglobin levels (mean decrease of 0.6 g/dL) that are frequently transient

Thrombocytopenia

  • Cases of thrombocytopenia, including immune thrombocytopenic purpura (ITP), have been reported with the use of TYSABRI in the postmarketing setting. Symptoms of thrombocytopenia may include easy bruising, abnormal bleeding, and petechiae. Delay in the diagnosis and treatment of thrombocytopenia may lead to serious and life-threatening sequelae. If thrombocytopenia is suspected, TYSABRI should be discontinued
  • Cases of neonatal thrombocytopenia, at times associated with anemia, have been reported in newborns with in utero exposure to TYSABRI. A CBC should be obtained in neonates with in utero exposure to TYSABRI

Adverse Reactions

  • The most common adverse reactions reported at an incidence of ≥10% with TYSABRI and ≥2% difference with placebo were headache (38% vs 33%), fatigue (27% vs 21%), infusion reactions (24% vs 18%), urinary tract infections (21% vs 17%), arthralgia (19% vs 14%), depression (19% vs 16%), pain in extremity (16% vs 14%), rash (12% vs 9%), gastroenteritis (11% vs 9%), and vaginitis (10% vs 6%)
  • The most frequently reported serious adverse reactions in Study MS1 were infections (3.2% vs 2.6% placebo), including urinary tract infection (0.8% vs 0.3%) and pneumonia (0.6% vs 0%), acute hypersensitivity reactions (1.1% vs 0.3%, including anaphylaxis/anaphylactoid reaction [0.8% vs 0%]), depression (1.0% vs 1.0%, including suicidal ideation or attempt [0.6% vs 0.3%]), and cholelithiasis (1.0% vs 0.3%)
  • Based on animal data, TYSABRI may cause fetal harm. TYSABRI should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus

Please see full Prescribing Information, including Boxed Warning.

AFFIRM=NAtalizumab Safety and EFFIcacy in Relapsing-Remitting Multiple Sclerosis; IV=intravenous; PPMS=primary progressive multiple sclerosis; SPMS=secondary progressive multiple sclerosis; PRMS=progressive relapsing multiple sclerosis; ARR=annualized relapse rate; RRMS=relapsing-remitting multiple sclerosis; AEs=adverse events; SAE=serious adverse event; MedDRA=Medical Dictionary for Regulatory Activities; CI=confidence interval; QoL=quality of life; EDSS=Expanded Disability Status Scale; DMTs=disease-modifying therapies.

 

References: 1. TYSABRI Prescribing Information. Cambridge, MA: Biogen. 2. Polman CH, O’Connor PW, Havrdova E, et al; for the AFFIRM investigators. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006;354(9):899-910. 3. Butzkueven H, Kappos L, Wiendl H et al. Long-term safety and effectiveness of natalizumab treatment in clinical practice: 10 years of real-world data from the TYSABRI Observational Program (TOP). J Neurol Neurosurg Psychiatry. 2020;91(6):660-668.

 

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