FDA-Approved Medications: New Data on Previously Approved Medications: Infused Medications
- 300 mg given via one-hour IV infusion every four weeks
- Approved in 2004 for relapsing forms of MS
Tysabri® (natalizumab) is a monoclonal antibody that acts against a molecule involved in the activation and function of lymphocytes, immune system cells produced to fight infection and disease. Tysabri also acts against the passage of lymphocytes into the central nervous system (CNS), which consists of the brain, spinal cord, and optic nerves.
The FDA approved Tysabri in 2004 based on positive results in the Phase III AFFIRM trial. Tysabri was voluntarily withdrawn from the market in 2005, after three cases of progressive multifocal leukoencephalopathy (PML), a rare but potentially fatal brain infection caused by the JC virus, were identified in patients taking the medication. Tysabri became available again in 2006, based on the implementation of a comprehensive risk-management program that includes testing potential Tysabri users to see if they have anti-JC virus antibodies.30
In an attempt to reduce the risk of PML, some clinicians are extending the interval between Tysabri doses, adopting a personalized dosing strategy that has been used to mitigate the adverse effects of extra-strength antibiotics and other medications.31 As more physicians stretch out the time between doses beyond the recommended four weeks, researchers decided to assess how this risk-reduction approach affects the medication’s therapeutic effects.4, 31
Investigators leading a two-year study are recording several measures of disease progression in 61 adults with MS who had no disease activity in the 12 months before enrollment. Treatment intervals are being adjusted to maintain the lowest therapeutic concentration of Tysabri (10 mcg/mL) for each patient before the next dose is given.
At the time interim study results were released, the 10 mcg/mL level had been maintained with extended dosing intervals of five to seven weeks in 84% of patients. No gadolinium-enhanced lesions or new or enlarging T2 lesions had been reported. Also, Expanded Disability Status Scale and MS Functional Composite scores had not increased, and serum levels of neurofilament light, an important indicator of MS disease activity, had remained low.
While biomarkers suggested some degree of disease activity among a subset of patients, the findings suggest that Tysabri dosing intervals can be safely expanded on a patient-by-patient basis.31
Other researchers recently found greater cognitive improvement among people who started Tysabri early in the course of their MS than in individuals whose treatment was delayed. The findings suggest that the earlier treatment can be started, the greater the chances of maintaining a patient’s cognitive function, researchers said.
A total of 2,069 patients with relapsing MS who were treated with Tysabri for at least 12 months were followed at 58 neurology clinics across Sweden. The participants were divided into two groups: those who started treatment within three years after MS onset, and those who started treatment later. Symbol Digit Modalities Test (SDMT) scores were collected at the start of Tysabri therapy, at six months and at one year after the start of treatment, and annually thereafter.
SDMT scores improved overall in both groups across the median 72-month follow-up, but the rate of improvement was an average of 0.38 points per year lower in the late-treatment group compared with patients who started treatment early.
When SDMT scores were examined by age, no difference in score trajectory was noted among patients younger than age 36 years, regardless of when they started treatment. Among patients aged 36 and older, however, SDMT score improvements were on average 0.45 points lower per year of follow-up among late-treated patients vs. early-treated subjects.
Of note, individuals who started Tysabri early had fewer relapses (1.91 vs 3.2) and modestly higher SDMT scores (52 vs 50) in the year before starting Tysabri early, compared with late-treated patients.32
Tysabri has long-term effectiveness in delaying relapses and slowing disability progression among people with relapsing-remitting MS, another ongoing study suggests.
The Tysabri Observational Program (TOP), begun by the medication’s manufacturer after Tysabri was approved by the FDA in 2004, is an open-label, multinational, prospective study that assesses the efficacy and safety of Tysabri in real-world clinical settings. As of November 2017, the continuing study included 6,148 patients with RRMS who received or are still receiving Tysabri. Median exposure to the medication was 3.3 years, and nearly 500 patients received Tysabri for eight years or longer. Median follow-up was 62 months as of the November 2017 review.
During the analysis, the annualized relapse rate (ARR) for patients on Tysabri fell from 1.99 in the year before treatment initiation to 0.15. Of note, ARRs for individuals taking Tysabri were significantly lower among patients with baseline Expanded Disability Status Scale scores of 3.0 or less, having taken two or fewer prior disease-modifying therapies, or no more than one relapse in the year prior to treatment.
Additionally, EDSS scores were stable throughout the analysis. At 10 years, the cumulative probability of 24-week confirmed disability worsening was 27.8%, and the cumulative probability of 24-week confirmed disability improvement was 33.1%. Of the 5,179 patients with baseline EDSS scores of 2.0 or higher, 1,210 (23.4%) experienced a confirmed disability improvement event.
The safety profile of Tysabri was consistent with adverse events (AE) reported in clinical trials. One or more serious AE was reported in 829 patients (13.5%). Infection was the most common AE, reported by 4.1% of patients. PML occurred in 53 patients (0.9%), while breast cancer and other malignancies occurred in 1.1%.33
Meanwhile, a recent Italian study found that use of Tysabri during pregnancy is associated with a lower risk of relapse but a greater incidence of newborn anemia compared to stopping the agent before conceiving.
Researchers followed 84 expectant mothers who were receiving Tysabri at 19 MS centers. Participants were divided into three groups: women whose last Tysabri infusion occurred before their last menstrual period (Group 0), those who were last infused during the first trimester of pregnancy (Group 1), and those who continued treatment throughout pregnancy (Group 2).
Annualized relapse rates (ARR) during pregnancy were 1.06 among Group 0 expectant mothers, 0.49 for those in Group 2, and 0.09 for women in Group 3. Among the women who restarted Tysabri after giving birth, ARRs 12 months postpartum were 0.39 for women in Group 0 and 0.23 for women in Group 1.
Researchers also analyzed data on the 94 infants who were born during the study and compared pregnancy outcomes among groups. No differences in mean gestational age or birthweight were found. However, major and minor malformations were reported in seven infants in Groups 1 and 2 (women who stopped natalizumab in early pregnancy or continued throughout), compared with one in Group 0 (women who stopped before pregnancy). Anemia was found in five newborns from mothers in Group 2, including three infants who were born prematurely.
The researchers commented that continuing Tysabri during pregnancy “is associated with lower risk of relapses compared to wash-out and early interruption. No worrisome adverse events emerged in newborns. Occurrence of anemia is consistent with previous findings and may be biased by prematurity.”34
Please note that women who are pregnant or are planning to become pregnant, while considering or taking a DMT, are advised to consult their physician.