Natalizumab extended interval administration

Abstract

Offering extended interval administration of natalizumab. [Solution] Provided herein are methods for reducing the risk of developing progressive multifocal leukemia in patients receiving natalizumab therapy by switching to an extended interval dosing (EID) schedule, in some embodiments. In one embodiment, a method is provided for improving the safety of chronic natalizumab therapy, the method comprising determining whether a patient has at least one risk factor for PML, and, in the presence of at least one risk factor, administering natalizumab to the patient on an extended interval dosing (EID) schedule with intervals of at least 5 weeks.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Applications No. 62 / 750,184 filed October 24, 2018; No. 62 / 717,543 filed August 10, 2018; No. 62 / 608,048 filed December 20, 2017; and No. 62 / 577,671 filed October 26, 2017, whose entire disclosure is incorporated by reference and for all purposes. [Background technology]

[0002] Natalizumab is a humanized monoclonal IgG4 antibody that inhibits lymphocyte migration across the blood-brain barrier by blocking the interaction between very slow antigen (VLA)-4 and vascular cell adhesion molecule (VCAM)-1, and by reducing inflammatory lesions. Progressive multifocal leukoencephalopathy (PML), opportunistic infections caused by John Cunningham virus (JCV), which occur only in immunocompromised patients, have affected a small group of patients using natalizumab. [Overview of the project] [Problems that the invention aims to solve]

[0003] This specification provides methods for improving the safety of chronic natalizumab therapy, for example, by using extended interval dosing (EID) of natalizumab to reduce the risk of developing PML in patients at risk. This disclosure shows that administration of natalizumab on an EID schedule (e.g., single doses at least every 5 weeks) may reduce the risk of developing PML and be as effective as standard interval dosing (SID, i.e., single doses every 4 weeks). In certain embodiments, EID of natalizumab reduces the risk of developing PML in patients who were seronegative for anti-JCV antibodies before initiation of natalizumab treatment but were later tested to be seronegative for anti-JCV antibodies during a standard 4-week interval course of natalizumab treatment. The methods described herein reduce the risk of developing PML without substantially impairing efficacy. In some embodiments, the EID schedule has intervals of at least 5 to 8 weeks. In some embodiments, the EID schedule has intervals of at least 5 to 7 weeks. In some embodiments, for patients with a weight range of less than 100 kg, the EID schedule has intervals of 6 weeks or less. In some embodiments, for patients with a weight range of less than 80 kg, the EID schedule has intervals of 6 weeks or less. In some embodiments, for patients with a weight range of less than 60 kg, the EID schedule has intervals of 7 weeks or less. In some embodiments, the EID schedule has intervals of 6 weeks or less (for example, at least 5 to 6 weeks or less). [Means for solving the problem]

[0004] In one embodiment, a method is provided for improving the safety of chronic natalizumab therapy, the method comprising determining whether a patient has at least one risk factor for PML, and administering natalizumab to the patient in an extended interval dosing (EID) schedule of at least 5 weeks apart, in the presence of at least the risk factor. The patient may have already received chronic treatment with natalizumab for a particular condition, or may have initiated treatment with natalizumab for a condition of interest. In some embodiments, the risk factor includes prior immunosuppression in the patient. In some embodiments, the risk factor includes the presence of anti-JCV antibodies in the patient. In some embodiments, the risk factor includes having an anti-JCV antibody index level (e.g., mean index level) greater than 0.9, greater than 1.0, greater than 1.1, greater than 1.2, greater than 1.3, greater than 1.4, or greater than 1.5. In some embodiments, the risk factor includes the length of any of the previous natalizumab therapy, such as at least about 6, 12, 18, 24, 30, or 36 months. In some embodiments, the EID schedule has intervals of at least 5 to 8 weeks. In some embodiments, the EID schedule has intervals of at least 5 to 7 weeks. In some embodiments, for patients with a weight range of less than 100 kg, the EID schedule has intervals of 6 weeks or less. In some embodiments, for patients with a weight range of less than 80 kg, the EID schedule has intervals of 6 weeks or less. In some embodiments, for patients with a weight range of less than 60 kg, the EID schedule has intervals of 7 weeks or less. In some embodiments, the EID schedule has intervals of 6 weeks or less (for example, at least 5 to 6 weeks).

[0005] In certain embodiments, this method includes determining the anti-JCV antibody status of a patient receiving or initiating chronic treatment with natalizumab, and, if the patient is serologically positive for JCV antibodies, administering natalizumab to the patient in an EID schedule with at least 5-week intervals. In some embodiments, the EID schedule has intervals of at least 5 to 8 weeks. In some embodiments, the EID schedule has intervals of at least 5 to 7 weeks. In some embodiments, for patients with a weight range of less than 100 kg, the EID schedule has intervals of 6 weeks or less. In some embodiments, for patients with a weight range of less than 80 kg, the EID schedule has intervals of 6 weeks or less. In some embodiments, for patients with a weight range of less than 60 kg, the EID schedule has intervals of 7 weeks or less. In some embodiments, the EID schedule has intervals of 6 weeks or less (e.g., at least 5 to 6 weeks).

[0006] Additional aspects of the present disclosure provide a method for reducing the risk of developing progressive multifocal leukemia (PML) in subjects, the method comprising: identifying low-PML-risk subjects receiving natalizumab therapy on a standard interval dosing (SID) schedule of 4 weeks; determining whether the subjects have at least one risk factor for PML, for example, if the subjects were switched from low-PML-risk subjects to high-PML-risk subjects during natalizumab therapy, and if the control was switched to high-PML-risk subjects, identifying high-PML-risk subjects for natalizumab therapy on an EID schedule of at least 5 weeks. In some embodiments, the EID schedule has intervals of at least 5 to 8 weeks. In some embodiments, the EID schedule has intervals of at least 5 to 7 weeks. In some embodiments, for patients with a weight range of less than 100 kg, the EID schedule has intervals of 6 weeks or less. In some embodiments, for patients with a weight range of less than 80 kg, the EID schedule has intervals of 6 weeks or less. In some embodiments, for patients with a weight range of less than 60 kg, the EID schedule has intervals of 7 weeks or less. In some embodiments, the EID schedule has intervals of 6 weeks or less (e.g., at least 5 to 6 weeks or less).

[0007] Other aspects of the present disclosure provide a method for reducing the risk of developing PML in a subject, the method comprising administering a therapeutically effective dose of natalizumab to a subject in a 4-week interval SID schedule, the subject being a low-PML-risk subject, determining whether the subject has been switched from a low-PML-risk subject to a high-PML-risk subject during natalizumab therapy, and, if the subject has been switched to a high-PML-risk subject, administering a therapeutically effective dose of natalizumab to the subject in an EID schedule at least 5 weeks apart. In some embodiments, the EID schedule has intervals of at least 5 to 8 weeks. In some embodiments, the EID schedule has intervals of at least 5 to 7 weeks. In some embodiments, for patients with a weight range of less than 100 kg, the EID schedule has intervals of 6 weeks or less. In some embodiments, for patients with a weight range of less than 80 kg, the EID schedule has intervals of 6 weeks or less. In some embodiments, for patients with a weight range of less than 60 kg, the EID schedule has intervals of 7 weeks or less. In some embodiments, the EID schedule has intervals of 6 weeks or less (for example, at least 5 to 6 weeks).

[0008] Further embodiments of this disclosure provide a method for reducing the risk of developing PML in subjects, the method comprising identifying subjects for natalizumab therapy in an EID schedule at intervals of at least 5 weeks, wherein subjects are tested for seropositive for anti-JCV antibodies and are receiving natalizumab therapy in an SID schedule at intervals of 4 weeks. In some embodiments, the EID schedule has intervals of at least 5 to 8 weeks. In some embodiments, the EID schedule has intervals of at least 5 to 7 weeks. In some embodiments, for patients with a weight range of less than 100 kg, the EID schedule has intervals of 6 weeks or less. In some embodiments, for patients with a weight range of less than 80 kg, the EID schedule has intervals of 6 weeks or less. In some embodiments, for patients with a weight range of less than 60 kg, the EID schedule has intervals of 7 weeks or less. In some embodiments, the EID schedule has intervals of 6 weeks or less (e.g., at least 5 to 6 weeks or less).

[0009] Further embodiments of this disclosure provide a method for reducing the risk of developing PML in a subject, the method comprising administering a therapeutically effective dose of natalizumab therapy to the subject in an EID schedule at intervals of at least 5 weeks, wherein the subject has been tested for serological positivity for anti-JCV antibodies and is receiving natalizumab therapy in an SID schedule at intervals of 4 weeks. In some embodiments, the EID schedule has intervals of at least 5 to 8 weeks. In some embodiments, the EID schedule has intervals of at least 5 to 7 weeks. In some embodiments, for patients with a weight range of less than 100 kg, the EID schedule has intervals of 6 weeks or less. In some embodiments, for patients with a weight range of less than 80 kg, the EID schedule has intervals of 6 weeks or less. In some embodiments, for patients with a weight range of less than 60 kg, the EID schedule has intervals of 7 weeks or less. In some embodiments, the EID schedule has intervals of 6 weeks or less (e.g., at least 5 to 6 weeks or less).

[0010] Further embodiments of this disclosure provide a method for reducing the risk of developing PML in subjects, the method comprising identifying subjects who have been tested for serological positivity for anti-JCV antibodies and are receiving natalizumab therapy on a 4-week interval SID schedule, and administering a therapeutically effective dose of natalizumab to the subjects on an EID schedule at least 5-week intervals. In some embodiments, the EID schedule has intervals of at least 5 to 8 weeks. In some embodiments, the EID schedule has intervals of at least 5 to 7 weeks. In some embodiments, for patients with a weight range of less than 100 kg, the EID schedule has intervals of 6 weeks or less. In some embodiments, for patients with a weight range of less than 80 kg, the EID schedule has intervals of 6 weeks or less. In some embodiments, for patients with a weight range of less than 60 kg, the EID schedule has intervals of 7 weeks or less. In some embodiments, the EID schedule has intervals of 6 weeks or less (e.g., at least 5 to 6 weeks).

[0011] In one embodiment, the present invention provides a method for improving the safety of chronic natalizumab therapy in patients in need thereof, the method comprising determining whether the patient has at least one risk factor for progressive multifocal encephalopathy (PML), and, in the presence of the at least one risk factor, administering natalizumab to the patient in a dose of 300 milligrams in an EID schedule with intervals of at least 5 weeks and no more than 7 weeks, where the patient's weight is approximately 40 kg to approximately 80 kg. In some embodiments, for patients with a weight range of less than 80 kg, the EID schedule has intervals of 6 weeks or less. In some embodiments, for patients with a weight range of less than 60 kg, the EID schedule has intervals of 7 weeks or less. In some embodiments, the EID schedule has intervals of 6 weeks or less (e.g., at least 5 to 6 weeks or less).

[0012] In another embodiment, the present invention provides a method for administering natalizumab therapy to a patient in need thereof, the method comprising administering natalizumab therapy in an EID schedule with a dose of 300 milligrams at intervals of at least 5 weeks and no more than 7 weeks, wherein: a. the patient has a weight range of 40 kg to less than 80 kg; b. the risk of PML with natalizumab therapy is reduced compared to natalizumab therapy on an SID schedule. In some embodiments, for patients with a weight range of less than 80 kg, the EID schedule has intervals of 6 weeks or less. In some embodiments, for patients with a weight range of less than 60 kg, the EID schedule has intervals of 7 weeks or less. In some embodiments, the EID schedule has intervals of 6 weeks or less (e.g., at least 5 to 6 weeks or less).

[0013] In another embodiment, the present invention provides a method for improving the safety of chronic natalizumab therapy in patients in need thereof, the method comprising determining whether the patient has at least one risk factor for progressive multifocal encephalopathy (PML), and, in the presence of the at least one risk factor, administering natalizumab to the patient in doses equivalent to 3.75 to 7.5 mg of natalizumab per kg of the patient's body weight, in an EID schedule with intervals of at least 5 weeks and no more than 8 weeks. In some embodiments, the EID schedule has intervals of at least 5 to 7 weeks. In some embodiments, for patients with a body weight range of less than 100 kg, the EID schedule has intervals of 6 weeks or less. In some embodiments, for patients with a body weight range of less than 80 kg, the EID schedule has intervals of 6 weeks or less. In some embodiments, for patients with a body weight range of less than 60 kg, the EID schedule has intervals of 7 weeks or less. In some embodiments, the EID schedule has intervals of 6 weeks or less (e.g., at least 5 to 6 weeks).

[0014] In another embodiment, the present invention provides a method for administering natalizumab therapy to a patient in need thereof, the method comprising administering natalizumab therapy to the patient in an EID schedule with intervals of at least 5 weeks and no more than 8 weeks, at a dose equivalent to 3.75 to 7.5 mg of natalizumab per kg of the patient's body weight, where the PML risk of natalizumab therapy is reduced compared to natalizumab therapy in an SID schedule. In some embodiments, the EID schedule has intervals of at least 5 to 7 weeks. In some embodiments, for patients with a body weight range of less than 100 kg, the EID schedule has intervals of 6 weeks or less. In some embodiments, for patients with a body weight range of less than 80 kg, the EID schedule has intervals of 6 weeks or less. In some embodiments, for patients with a body weight range of less than 60 kg, the EID schedule has intervals of 7 weeks or less. In some embodiments, the EID schedule has intervals of 6 weeks or less (e.g., at least 5 to 6 weeks).

[0015] In another embodiment, the present invention provides a method for administering natalizumab therapy to a patient in need thereof, the method comprising administering natalizumab therapy for 12 months on an SID schedule, and then administering natalizumab therapy on an EID schedule. In some embodiments, the EID schedule has intervals of at least 5 to 8 weeks. In some embodiments, the EID schedule has intervals of at least 5 to 7 weeks. In some embodiments, for patients with a weight range of less than 100 kg, the EID schedule has intervals of 6 weeks or less. In some embodiments, for patients with a weight range of less than 80 kg, the EID schedule has intervals of 6 weeks or less. In some embodiments, for patients with a weight range of less than 60 kg, the EID schedule has intervals of 7 weeks or less. In some embodiments, the EID schedule has intervals of 6 weeks or less (e.g., at least 5 to 6 weeks or less).

[0016] In another embodiment, the present invention provides a method for improving the safety of chronic natalizumab therapy in patients in need thereof, the method comprising determining whether the patient has at least one risk factor for progressive multifocal encephalopathy (PML), and administering natalizumab to the patient in an EID schedule including intervals of at least 5 weeks in the presence of the at least one risk factor. In some embodiments, the at least one risk factor includes prior immunosuppression in the patient. In some embodiments, the at least one risk factor includes or further includes the presence of serum anti-JCV antibodies in the patient. In some embodiments, the at least one risk factor includes an anti-JCV antibody index level (e.g., mean index level) greater than 0.9, greater than 1.0, greater than 1.1, greater than 1.2, greater than 1.3, greater than 1.4, or greater than 1.5. In some embodiments, the EID schedule has intervals of at least 5 weeks to 8 weeks or less. In some embodiments, the EID schedule has intervals of at least 5 weeks to 7 weeks or less. In some embodiments, for patients with a weight range of less than 100 kg, the EID schedule has intervals of 6 weeks or less. In some embodiments, for patients with a weight range of less than 80 kg, the EID schedule has intervals of 6 weeks or less. In some embodiments, for patients with a weight range of less than 60 kg, the EID schedule has intervals of 7 weeks or less. In some embodiments, the EID schedule has intervals of 6 weeks or less (for example, at least 5 to 6 weeks or less).

[0017] In some embodiments, the above at least one risk factor includes the presence of anti-JCV antibodies in the patient, and the determination step includes determining the patient's anti-JCV antibody status and, if the patient is serologically positive for JCV antibodies, administering natalizumab to the patient in an EID schedule at intervals of at least 5 weeks (e.g., an EID schedule at intervals of at least 5 weeks to 8 weeks or less). In some embodiments, the EID schedule has intervals of at least 5 weeks to 7 weeks or less. In some embodiments, the method includes administering natalizumab to the patient in an EID schedule at intervals of 6 weeks. In some embodiments, the patient has an anti-JCV antibody index greater than 0.9. In some embodiments, the patient has an anti-JCV antibody index level greater than 1.5.

[0018] In some embodiments, if at least one risk factor is the length of prior natalizumab treatment and the patient has received natalizumab therapy for more than 6 months (or at least 12 months), the method includes administering natalizumab to the patient in an EID schedule with intervals of at least 5 weeks. In some embodiments, if the above at least one risk factor is the length of prior natalizumab treatment and the patient has received natalizumab therapy for more than 6 months (or at least 12 months), the method includes administering natalizumab to the patient in an EID schedule with intervals of at least 5 weeks. In some embodiments, the EID schedule has intervals of at least 5 weeks to 8 weeks or less. In some embodiments, the EID schedule has intervals of at least 5 weeks to 7 weeks or less. In some embodiments, for patients with a weight range of less than 100 kg, the EID schedule has intervals of 6 weeks or less. In some embodiments, for patients with a weight range of less than 80 kg, the EID schedule has intervals of 6 weeks or less. In some embodiments, for patients with a weight range of less than 60 kg, the EID schedule has intervals of 7 weeks or less. In some embodiments, the EID schedule has intervals of 6 weeks or less (e.g., at least 5 to 6 weeks or less).

[0019] In some embodiments, natalizumab therapy for more than 6 months is natalizumab therapy for more than 6 months on the SID schedule. In some embodiments, the EID schedule interval is from 5 weeks to 8 weeks. In some embodiments, the EID schedule interval is from 5 to 6 weeks. In some embodiments, the EID schedule interval is 6 weeks.

[0020] In some embodiments, the patient weighs less than about 120 kg; or the patient weighs less than about 100 kg; or the patient weighs less than about 80 kg; or the patient weighs less than about 60 kg; or the patient weighs from about 40 kg to less than about 120 kg; or the patient weighs from about 40 kg to less than about 100 kg; or the patient weighs from about 40 kg to less than about 80 kg; or the patient weighs from about 40 kg to less than about 60 kg.

[0021] In some embodiments, the patient weighs from about 40 kg to about 80 kg, and the EID schedule has an interval of at least 5 weeks and 6 weeks or less. In some embodiments, the patient weighs from about 40 kg to about 80 kg, and the EID schedule has an interval of 6 weeks. In some embodiments, the patient weighs from about 40 kg to about 60 kg, and the EID schedule has an interval of 6 weeks.

[0022] In some embodiments, the EID schedule includes a dose of 300 milligrams. In some embodiments, the EID schedule includes a dose corresponding to 3.75 - 7.5 mg of natalizumab per kg of the patient's body weight. In some embodiments, the patient has an autoimmune disease. In some embodiments, the autoimmune disease is MS. In some embodiments, the autoimmune disease is an inflammatory bowel disease. In some embodiments, the autoimmune disease is Crohn's disease. In some embodiments, the patient has been diagnosed with epilepsy or has epilepsy.

[0023] In another embodiment, the present invention provides a method for administering natalizumab therapy to a patient in need thereof, the method comprising administering natalizumab therapy on an EID schedule, where the patient's weight range is 40 kg to less than 80 kg; and the PML risk of natalizumab therapy is reduced compared to natalizumab therapy on an SID schedule. In some cases, the EID schedule includes a dose of 300 mg. In some embodiments, the EID schedule includes a dose equivalent to 3.75 to 7.5 mg of natalizumab per kg of the patient's weight. In some embodiments, the EID schedule has an interval of at least 5 to 8 weeks. In some embodiments, the EID schedule has an interval of at least 5 to 7 weeks. In some embodiments, for patients with a weight range of less than 80 kg, the EID schedule has an interval of 6 weeks or less. In some embodiments, for patients with a weight range of less than 60 kg, the EID schedule has an interval of 7 weeks or less. In some embodiments, the EID schedule has an interval of 6 weeks or less (e.g., at least 5 to 6 weeks).

[0024] In some embodiments, examples, cases, or examples described herein, the patient's weight is approximately 40 kg to approximately 80 kg, and the EID schedule has intervals of at least 5 weeks and no more than 6 weeks. In some embodiments, the patient's weight is approximately 40 kg to approximately 80 kg, and the EID schedule has intervals of 6 weeks. In some embodiments, the patient's weight is approximately 40 kg to approximately 60 kg, and the EID schedule has intervals of at least 5 weeks and no more than 7 weeks. In some embodiments, the patient's weight is approximately 40 kg to approximately 60 kg, and the EID schedule has intervals of 6 weeks.

[0025] In certain preferred embodiments, cases, or examples described herein, the EID schedule maintains a mean trough α4-integrin receptor saturation of more than 60% in the EID patient population. In certain preferred embodiments, cases, or examples described herein, the EID schedule maintains a mean trough α4-β1 integrin receptor saturation of more than 60% in the EID patient population. In some embodiments, cases, or examples described herein, the EID schedule maintains a mean trough α4-integrin receptor saturation of more than 50% in the EID patient population. In some embodiments, cases, or examples described herein, the EID schedule maintains a mean trough α4-β1 integrin receptor saturation of more than 50% in the EID patient population. In some embodiments, cases, or examples described herein, the EID schedule maintains a mean trough α4-integrin receptor saturation of more than 55% in the EID patient population. In some embodiments, cases, or examples described herein, the EID schedule maintains a mean trough α4-β1 integrin receptor saturation of more than 55% in the EID patient population. In some of the embodiments, cases, or examples described herein, the EID schedule maintains a mean trough α4-integrin receptor saturation of more than 65% in the EID patient population. In some of the embodiments, cases, or examples described herein, the EID schedule maintains a mean trough α4β1 integrin receptor saturation of more than 65% in the EID patient population.

[0026] In some of the embodiments, examples, cases, or examples described herein, the efficacy of natalizumab therapy on an EID schedule is reduced by 20% or less compared to natalizumab therapy on a SID schedule. In some of the embodiments, examples, cases, or examples described herein, the risk of Gd+ lesions at week 48 (or week 72) with natalizumab therapy on an EID schedule is increased by approximately 5% or 10% or less, the mean number of Gd+ lesions predicted at week 48 (or week 72) with natalizumab therapy on an EID schedule is increased by approximately 0.5, 0.65, or 1 or less with the EID schedule, and / or the cumulative probability of clinical relapse at week 48 (or week 72) with natalizumab therapy is increased by approximately 5%, 10%, 15%, or 20% or less with the EID schedule.

[0027] In some of the embodiments, cases, or examples described herein, the method involves administering natalizumab on an EID schedule for at least 6 months, at least 1 year, at least 18 months, at least 2 years, or at least 5 years. In some of the embodiments, cases, cases or examples described herein, the method involves administering natalizumab on an EID schedule for less than 72 weeks (e.g., at least 6 months to less than 72 weeks). [Brief explanation of the drawing]

[0028] [Figure 1A] Figure 1A shows a plot of Kaplan-Meier estimates of time to PML over 72 months for anti-JCV antibody-positive patients grouped according to the administration schedule of Example 1. Patients in the SID cohort (solid line) and patients in the EID cohort (dashed line) are shown. [Figure 1B] Figure 1B shows a plot of Kaplan-Meier estimates of time to PML for anti-JCV antibody-positive patients without prior immunosuppressive treatment, grouped according to the administration schedule described in Example 1. Patients from the SID cohort (solid line) and patients from the EID cohort (dashed line) are shown. [Figure 1C]Figure 1C shows a plot of Kaplan-Meier estimates of time to PML in anti-JCV antibody-positive patients previously treated with immunosuppressants, grouped according to the dosing schedule described in Example 1. Patients from the SID cohort (solid line) and patients from the EID cohort (dashed line) are shown. [Figure 1D] Figure 1D shows a plot of Kaplan-Meier estimates of time to PML over 120 months for anti-JCV antibody-positive patients grouped according to the dosing schedule described in Example 1. Patients in the SID cohort (solid line) and patients in the EID cohort (dashed line) are shown. The model includes age, sex, prior use of IS, EID / SID group, and calendar year at the start of natalizumab treatment as covariates. EID = extended interval dosing. IS = immunosuppressant. KM = Kaplan-Meier. PML = progressive multifocal leukoencephalopathy. SID = standard interval dosing. *EID vs. SID. †Number of patients still under study who did not have PML at the end of the specified time. ‡Cumulative number of PML cases at the end of the specified time. [Figure 2A] Figure 2A shows a plot of Kaplan-Meier estimates of time to PML over 72 months for anti-JCV antibody-positive patients grouped according to the dosing schedule described in Example 2. Patients from the SID cohort (solid line) and patients from the EID cohort (dashed line) are shown. [Figure 2B] Figure 2B shows a plot of Kaplan-Meier estimates of time to PML for anti-JCV antibody-positive patients without prior immunosuppressant treatment, grouped according to the administration schedule described in Example 2. Patients from the SID cohort and EID cohort (dashed lines) are shown. [Figure 2C] Figure 2C shows a plot of Kaplan-Meier estimates of time to PML in anti-JCV antibody-positive patients previously treated with immunosuppressants, grouped according to the administration schedule described in Example 2. Patients from the SID cohort (solid line) and patients from the EID cohort (dashed line) are shown. [Figure 2D]Figure 2D shows a plot of Kaplan-Meier estimates of time to PML over 120 months for anti-JCV antibody-positive patients grouped according to the dosing schedule described in Example 2. Patients in the SID cohort (solid line) and patients in the EID cohort (dashed line) are shown. The model includes age, sex, prior use of IS, EID / SID group, and calendar year at the start of natalizumab treatment as covariates. EID = extended interval dosing. IS = immunosuppressant. KM = Kaplan-Meier. PML = progressive multifocal leukoencephalopathy. SID = standard interval dosing. *EID vs. SID. †Number of patients still under study who did not have PML at the end of the specified time. ‡Cumulative number of PML cases at the end of the specified time. [Figure 3A] Figure 3A shows a plot of Kaplan-Meier estimates of time to PML over 72 months for anti-JCV antibody-positive patients grouped according to the dosing schedule described in Example 3. Patients in the SID cohort (solid line) and patients in the EID cohort (dashed line) are shown. [Figure 3B] Figure 3B shows a plot of Kaplan-Meier estimates of time to PML over 120 months for anti-JCV antibody-positive patients grouped according to the dosing schedule described in Example 3. Patients in the SID cohort (solid line) and patients in the EID cohort (dashed line) are shown. [Figure 3C] Figure 3C shows a plot of Kaplan-Meier estimates of time to PML for anti-JCV antibody-positive patients without prior immunosuppressant treatment, grouped according to the administration schedule described in Example 3. Patients from the SID cohort (solid line) and patients from the EID cohort (dashed line) are shown. [Figure 3D]Figure 3D shows a plot of Kaplan-Meier estimates of time to PML in anti-JCV antibody-positive patients previously treated with immunosuppressants, grouped according to the dosing schedule described in Example 3. Patients in the SID cohort (solid line) and patients in the EID cohort (dashed line) are shown. The model includes age, sex, prior use of IS, EID / SID group, and calendar year at the start of natalizumab treatment as covariates. EID = extended interval dosing. IS = immunosuppressant. KM = Kaplan-Meier. PML = progressive multifocal leukoencephalopathy. SID = standard interval dosing. *EID vs. SID. †Number of patients still under study who did not have PML at the end of the specified time. ‡Cumulative number of PML cases at the end of the specified time. [Figure 4] Figure 4 shows patient flow charts for primary, secondary, and tertiary PML risk analyses. To be included in any analysis, patients were not allowed to have medication gaps (defined as intervals of more than 12 weeks between two consecutive infusions) or overdoses (defined as intervals of less than 3 weeks between two consecutive infusions). EID = Extended interval infusion. JCV = JC virus. SID = Standard interval infusion. †Occurrence of at least one medication gap (interval of more than 12 weeks between two consecutive infusions) or overdose (interval of less than 3 weeks between two consecutive infusions). ‡Patient switched between SID and EID two or more times. [Figure 5] Figure 5 shows information on the administration history and risk factors for individual EID PML cases. IS = immunosuppressant. NA = unavailable. *Patients did not meet the primary analysis definition for EID based on having received more than 15 doses in the last 18 months. Note that the first diamond for all 13 patients represents the first infusion. The remaining diamonds represent SID infusions or EID infusions as shown. [Figure 6]Figure 6 shows a plot of Kaplan-Meier estimates of time to PML over 120 months for anti-JCV antibody-positive patients grouped according to EID definition 1b described in Example 6. Patients in the SID cohort (solid line) and patients in the EID cohort (dashed line) are shown. The model includes age, sex, prior use of IS, EID / SID group, and calendar year at initiation of natalizumab treatment as covariates. EID = extended interval dosing. IS = immunosuppressant. KM = Kaplan-Meier. PML = progressive multifocal leukoencephalopathy. SID = standard interval dosing. *EID vs. SID. (a) Number of patients still in study and who did not have PML at the end of the specified time. (b) Cumulative number of PML cases at the end of the specified time. [Figure 7] Figure 7 shows a plot of Kaplan-Meier estimates of time to PML over 120 months for anti-JCV antibody-positive patients grouped according to EID definition 2b described in Example 6. Patients in the SID cohort (solid line) and patients in the EID cohort (dashed line) are shown. The model includes age, sex, prior use of IS, EID / SID group, and calendar year at initiation of natalizumab treatment as covariates. EID = extended interval dosing. IS = immunosuppressant. KM = Kaplan-Meier. PML = progressive multifocal leukoencephalopathy. SID = standard interval dosing. *EID vs. SID. (a) Number of patients still in study and who did not have PML at the end of the specified time. (b) Cumulative number of PML cases at the end of the specified time. [Figure 8] Figure 8 shows a schematic diagram of the prospective study design described in Example 6. [Figure 9] Figure 9 shows the simulated mean natalizumab concentration-time profiles over 52 weeks, categorized by varying SID and EID drug regimens and body weight ranges. [Figure 10] Figure 10 is a box plot of simulated trough α-4 integrin saturation levels categorized by patient weight range. [Figure 11]Figure 11 shows a fitted curve of the probability of Gd+ lesion occurrence calculated as described in Example 6, Model 1. CI = Confidence Interval; GD+ = Gadolinium Enhancement; Q4W = Every 4 weeks; Q6W = Every 6 weeks; Q12W = Every 12 weeks. [Figure 12] Figure 12 shows the fitted curve for the probability of Gd+ lesion occurrence calculated as described in Example 6, Model 2. CI = Confidence Interval; GD+ = Gadolinium Enhancement; Q4W = Every 4 weeks; Q6W = Every 6 weeks; Q12W = Every 12 weeks. [Figure 13] Figure 13 shows fitted curves of the probability of clinical relapse calculated as described in Example 6, Model 3. CI = Confidence Interval; GD+ = Gadolinium Enhancement; Q4W = Every 4 weeks; Q6W = Every 6 weeks; Q12W = Every 12 weeks. [Figure 14] Figures 14A-C illustrate three planned analyses of PML risk, as well as the definitions of EID and SID used in Example 7. Each assumed patient describes a 2-year infusion history. A. Primary analysis: Test effect of the past 18 months of medication history on PML risk. Definitions: EID-1°: 15 or fewer infusions in the past 18 months (548 days); SID-1°: More than 15 infusions in the past 18 months (548 days). B. Secondary analysis: Test effect of any long-term EID on PML risk. Definitions: EID-2°: EID-2° infusions are preceded by 10 or fewer doses in the past 365 days, and EID-2° patients received EID-2° infusions for 6 months or more consecutively; SID-2° infusions are preceded by more than 10 doses in the past 365 days, and SID-2° patients received SID-2° infusions for 6 months or more consecutively. C. Third-order analysis: Study effect of administration history, mainly consisting of EID, on PML risk. Definitions: EID-3°: 10 or fewer infusions per year over the entire treatment period. SID-3°: More than 10 infusions per year over the entire treatment period. EID = extended interval administration; PML = progressive multifocal leukoencephalopathy; SID = standard interval administration. [Figure 15]Figure 15 illustrates a patient flowchart for primary, secondary, and tertiary PML risk analysis as described in Example 7. Abbreviations: EID = Extended Interval Dosing; JCV = JC virus; SID = Standard Interval Dosing. To be included in the analysis of Example 7, patients were not to experience any dosing gaps (defined as an interval of more than 12 weeks between two consecutive infusions) or overdoses (defined as an interval of less than 3 weeks between two consecutive infusions). *Number of registered patients as of June 1, 2017. †Occurrence of at least one dosing gap (interval between two consecutive infusions longer than 12 weeks) or overdose (interval between two consecutive infusions less than 3 weeks). ‡Patients switched between SID and EID two or more times. [Figure 16A] Figures 16A to 16C show plots of Kaplan-Meier estimates of the cumulative probability of PML in the EID group versus the SID group in the (A) primary, (B) secondary, and (3) tertiary analyses of Example 7. [Figure 16B] Figures 16A to 16C show plots of Kaplan-Meier estimates of the cumulative probability of PML in the EID group versus the SID group in the (A) primary, (B) secondary, and (3) tertiary analyses of Example 7. [Figure 16C] Figures 16A to 16C show plots of Kaplan-Meier estimates of the cumulative probability of PML in the EID group versus the SID group in the (A) primary, (B) secondary, and (3) tertiary analyses of Example 7. [Figure 17] Figure 17 shows the administration history and risk factor information for individual EID PML cases. IS = immunosuppressant; NA = unavailable; *Patients did not meet the primary analysis definition of EID based on having received more than 15 doses in the last 18 months. [Figure 18]Figure 18 shows the evaluation items and assessments for the NOVA study described in Example 8. *EID group only. †Includes TSQM (Treatment Satisfaction Questionnaire for Medication), Neuro-QoL (Quality of Life in Neurological Disorders) fatigue, MSIS-29 (Multiple Sclerosis Impact Scale), and EQ-5D-5L (EuroQol 5-D Questionnaire). ARR = Annual Relapse Rate. [Figure 19] Figure 19 illustrates the rationale for the study dose intervals described in Example 8. The shaded areas indicate the ranges of SID and EID dosing intervals in the NOVA study. SID 1° and EID 1°, SID 2° and EID 2°, and SID 3° and EID 3° describe the definitions of SID and EID for the primary, secondary, and tertiary analyses, respectively, regarding PML risk in the TOUCH analysis, as described by Zhovtis Ryerson L et al. (published in ACTRIMS); February 1-3, 2018; San Diego, CA. LB250. ADI = Mean Daily Intake. [Figure 20A]Figures 20A-20B show analyses suggesting the benefits of studying the risk of PML in patients switched from SID to EID. A. The treatment effect of natalizumab is greatest at 1 year. Patients with no clinical and radiological disease activity at 1 and 2 years after natalizumab treatment in AFFIRM. (Havrdova E, et al. Lancet Neurol. 2009;8:254-260;12) Absence of a combination of clinical and radiological measurements was defined as no relapse, no progression of disability (lasting 12 weeks), no Gd+ lesions, and new or expanding T2 high-intensity lesions. B. The risk of PML is low in the first year of treatment. To account for 12 missing data points in a pooled cohort (n=21,696) of patients treated with natalizumab from four large observational, open-label studies (STRATIFY, STRATA, TOP, and TYGRIS), the conditional probability of developing PML in each year of treatment is shown using the life table method with multiple complements. The box highlights the risk of PML during the first year of treatment. [Figure 20B] Figures 20A-20B show analyses suggesting the benefits of studying the risk of PML in patients switched from SID to EID. A. The treatment effect of natalizumab is greatest at 1 year. Patients with no clinical and radiological disease activity at 1 and 2 years after natalizumab treatment in AFFIRM. (Havrdova E, et al. Lancet Neurol. 2009;8:254-260;12) Absence of a combination of clinical and radiological measurements was defined as no relapse, no progression of disability (lasting 12 weeks), no Gd+ lesions, and new or expanding T2 high-intensity lesions. B. The risk of PML is low in the first year of treatment. To account for 12 missing data points in a pooled cohort (n=21,696) of patients treated with natalizumab from four large observational, open-label studies (STRATIFY, STRATA, TOP, and TYGRIS), the conditional probability of developing PML in each year of treatment is shown using the life table method with multiple complements. The box highlights the risk of PML during the first year of treatment. [Modes for carrying out the invention]

[0029] Natalizumab, marketed under the brand names TYSABRI® (BIOGEN®, MA), is an integrin receptor antagonist approved by the U.S. Food and Drug Administration (FDA) for the treatment of multiple sclerosis and Crohn's disease. The FDA-approved standard dosing (SD) regimen involves intravenous infusion of 300 milligrams (mg) every four weeks over approximately one hour. Within the patient population receiving natalizumab therapy, there is a small subpopulation that has developed progressive multifocal leukoencephalopathy (PML) (Plavina, T. et al. Ann Neurol 2014;76:802-12). While we do not wish to be bound by theory, both the therapeutic effect of natalizumab and the increased risk of PML are hypothesized to be due to natalizumab's inhibition of lymphocyte transport to the brain. While it has been hypothesized that the risks and efficacy of natalizumab are closely related, the inventors have surprisingly found that extending the interval between natalizumab administrations can enhance the safety of natalizumab treatment without any associated decrease in efficacy. Analysis of the TOUCH and PML databases described herein clearly demonstrates that in anti-JCV antibody-positive patients, EID treatment is associated with a lower risk of PML than SID treatment. Similar results are expected in patient subgroups with other risk factors or combinations of PML risk factors, such as patients who are anti-JCV antibody-negative, patients with unknown anti-JCV antibody status, patients with anti-JCV antibody index levels >0.9 or >1.5, patients with a history of immunosuppressant use, and / or patients who have received natalizumab treatment on an SID schedule for an extended period (e.g., more than 6 months). This disclosure provides a method for reducing the risk of PML by extending the interval between doses of natalizumab in patients who have a high PML risk condition and / or who are transitioning from a low PML risk condition to a high PML risk condition.

[0030] As used herein, extended interval dosing (EID) refers to the administration of natalizumab at intervals that extend beyond a standard interval dosing (SID) schedule of 300 mg every four weeks. An EID schedule should not exceed 12 doses of natalizumab within a 12-month period (1 month = 30 days), and typically does not exceed 11 or 10 doses within a 12-month period (1 month = 30 days). Therefore, an SID schedule must exceed 10 doses of natalizumab within a 12-month period, and typically exceeds 11 or 12 doses within a 12-month period. In some embodiments, the EID schedule interval for administering natalizumab (e.g., 300 mg dose) is at least 5 weeks (35 days). For example, the EID schedule interval may be at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, or at least 10 weeks. In some embodiments, the EID schedule interval is 5 to 12 weeks. For example, the EID scheduling interval may be 5-11 weeks, 5-10 weeks, 5-9 weeks, 5-8 weeks, 5-7 weeks, or 5-6 weeks. In some embodiments, the EID scheduling interval is 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, or 12 weeks. In some embodiments, the EID scheduling interval is 5 weeks and 1 day, 5 weeks and 2 days, 5 weeks and 3 days, 5 weeks and 4 days, 5 weeks and 5 days, or 5 weeks and 6 days. In some embodiments, the EID scheduling interval is 6 weeks and 1 day, 6 weeks and 2 days, 6 weeks and 3 days, 6 weeks and 4 days, 6 weeks and 5 days, or 6 weeks and 6 days. In some embodiments, the EID schedule is 7 weeks and 1 day, 7 weeks and 2 days, 7 weeks and 3 days, 7 weeks and 4 days, 7 weeks and 5 days, or 7 weeks and 6 days. In some embodiments, the EID scheduling interval is 8 weeks and 1 day, 8 weeks and 2 days, 8 weeks and 3 days, 8 weeks and 4 days, 8 weeks and 5 days, or 8 weeks and 6 days. In some embodiments, the EID scheduling interval is 9 weeks and 1 day, 9 weeks and 2 days, 9 weeks and 3 days, 9 weeks and 4 days, 9 weeks and 5 days, or 9 weeks and 6 days. In some embodiments, the EID scheduling interval is 10 weeks and 1 day, 10 weeks and 2 days, 10 weeks and 3 days, 10 weeks and 4 days, 10 weeks and 5 days, or 10 weeks and 6 days.In some embodiments, the EID scheduling interval is 11 weeks and 1 day, 11 weeks and 2 days, 11 weeks and 3 days, 11 weeks and 4 days, 11 weeks and 5 days, or 11 weeks and 6 days.

[0031] In some embodiments, the interval between EID schedules is longer than 4 weeks and less than 12 weeks. In some embodiments, the interval between EID schedules is at least 5 weeks and less than 12 weeks. In some embodiments, the interval between EID schedules is longer than 4 weeks and about 11 weeks or less. In some embodiments, the interval between EID schedules is at least 5 weeks and about 11 weeks or less. In some embodiments, the interval between EID schedules is longer than 4 weeks and 8 weeks or less. In some embodiments, the interval between EID schedules is at least 5 weeks and 8 weeks or less. In some embodiments, the interval between EID schedules is longer than 4 weeks and 7 weeks or less. In some embodiments, the interval between EID schedules is at least 5 weeks and 7 weeks or less. In some embodiments, the interval between EID schedules is longer than 4 weeks and 6 weeks or less. In some embodiments, the interval between EID schedules is at least 5 weeks and 6 weeks or less.

[0032] In some embodiments, the interval of the EID schedule depends on the patient's weight. For example, the EID schedule interval may be more than 4 weeks but less than 10 weeks, or more than 4 weeks but 8 weeks or less, for patients with a weight range of less than 60 kg. In some embodiments, the EID schedule interval may be more than 4 weeks but less than 10 weeks, or more than 4 weeks but 8 weeks or less, for patients with a weight range of 40 to 59 kg. Another example is that the EID schedule interval may be more than 4 weeks but less than 8 weeks, or more than 4 weeks but 8 weeks or less, for patients with a weight range of less than 60 kg. In some embodiments, the EID schedule interval may be more than 4 weeks but less than 7 weeks, for patients with a weight range of 40 to 59 kg. In some embodiments, the EID schedule interval may be more than 4 weeks but 7 weeks or less, for patients with a weight range of 40 to 59 kg. In some embodiments, the EID schedule interval may be more than 4 weeks but 7 weeks or less, for patients with a weight range of less than 60 kg. In some embodiments, the EID schedule interval may be more than 4 weeks but 7 weeks or less, for patients with a weight range of less than 60 kg. In some embodiments, for patients weighing less than 60 kg or in the weight range of 40 kg to less than 60 kg, the EID schedule interval is 6 weeks.

[0033] In some embodiments, the EID scheduling interval may be at least 5 weeks to less than 10 weeks, or at least 5 weeks to 8 weeks, for patients with a weight range of less than 60 kg. In some embodiments, the EID scheduling interval may be at least 5 weeks to less than 10 weeks, or at least 5 weeks to 8 weeks, for patients with a weight range of 40 to 59 kg. In some embodiments, the EID scheduling interval may be at least 5 weeks to less than 7 weeks, for patients with a weight range of 40 to 59 kg. In some embodiments, the EID scheduling interval may be at least 5 weeks to 7 weeks, for patients with a weight range of 40 to 59 kg. In some embodiments, the EID scheduling interval may be at least 5 weeks to 7 weeks, for patients with a weight range of 40 to 59 kg. In some embodiments, the EID scheduling interval may be at least 5 weeks to 7 weeks, for patients with a weight range of less than 60 kg.

[0034] As another example, the EID scheduling interval may be longer than 4 weeks but less than 8 weeks for patients with a weight range exceeding 59 kg. In some embodiments, the EID scheduling interval may be longer than 4 weeks but less than 8 weeks for patients with a weight range of 60 kg to less than 80 kg. In some embodiments, the EID scheduling interval may be at least 5 weeks to less than 8 weeks for patients with a weight range exceeding 59 kg. In some embodiments, the EID scheduling interval may be at least 5 weeks to less than 8 weeks for patients with a weight range of 60 kg to less than 8 kg. In some embodiments, the EID scheduling interval is 8 weeks or less for patients with a weight range of 60 kg or more. In some embodiments, the EID scheduling interval is 7 weeks or less for patients with a weight range of 60 kg or more. In some embodiments, the EID scheduling interval is 6 weeks or less for patients with a weight range of 60 kg or more.

[0035] As another example, the EID scheduling interval may be longer than 4 weeks but less than 7 weeks for patients with a weight range of at least 80 kg, or between 80 kg and less than 100 kg. In some embodiments, the EID scheduling interval may be at least 5 weeks but less than 7 weeks for patients with a weight range of at least 80 kg, or between 80 kg and less than 100 kg. As another example, the EID scheduling interval may be longer than 4 weeks but 6 weeks or less for patients with a weight range of at least 100 kg, or between 100 kg and less than 120 kg. In some embodiments, the EID scheduling interval may be at least 5 weeks but 6 weeks or less for patients with a weight range of at least 100 kg, or between 100 kg and less than 120 kg. In some embodiments, the EID scheduling interval is 7 weeks or less for patients with a weight range of 80 kg or more. In some embodiments, the EID scheduling interval is 6 weeks or less for patients with a weight range of 80 kg or more.

[0036] As another example, the EID scheduling interval may be longer than 4 weeks but no more than 6 weeks for patients with a weight range of less than 100 kg. In some embodiments, the EID scheduling interval may be longer than 4 weeks but no more than 6 weeks for patients with a weight range of 40 kg to less than 100 kg. In some embodiments, the EID scheduling interval may be at least 5 weeks to less than 7 weeks for patients with a weight range of less than 100 kg. In some embodiments, the EID scheduling interval may be at least 5 weeks to 6 weeks for patients with a weight range of less than 100 kg. In some embodiments, the EID scheduling interval may be at least 5 weeks to 6 weeks for patients with a weight range of 40 kg to less than 100 kg. In some embodiments, the EID scheduling interval is 6 weeks or less for patients with a weight range of 100 kg or more. In some embodiments, the EID scheduling interval is 5 weeks or less for patients with a weight range of 100 kg or more.

[0037] As another example, the EID scheduling interval may be longer than 4 weeks but no more than 6 weeks for patients with a weight range of less than 120 kg. In some embodiments, the EID scheduling interval may be longer than 4 weeks but no more than 6 weeks for patients with a weight range of 40 kg to less than 120 kg. In some embodiments, the EID scheduling interval may be at least 5 weeks to less than 7 weeks for patients with a weight range of less than 120 kg. In some embodiments, the EID scheduling interval may be at least 5 weeks to less than 6 weeks for patients with a weight range of less than 120 kg. In some embodiments, the EID scheduling interval may be at least 5 weeks to less than 6 weeks for patients with a weight range of 40 kg to less than 120 kg. In some embodiments, the EID scheduling interval may be about 5 weeks for patients with a weight range of 40 kg to less than 120 kg.

[0038] As another example, the EID scheduling interval may be at least 5 to 6 weeks for patients with a weight range of less than 80 kg. As yet another example, the EID scheduling interval may be at least 5 to 6 weeks for patients with a weight range of 40 kg to less than 80 kg. In some embodiments, the EID scheduling interval may be at least 5 to less than 7 weeks for patients with a weight range of less than 80 kg. In some embodiments, the EID scheduling interval may be at least 5 to less than 7 weeks for patients with a weight range of 40 kg to less than 80 kg. In some embodiments, the EID scheduling interval may be at least 5 to less than 8 weeks for patients with a weight range of less than 80 kg. In some embodiments, the EID scheduling interval may be at least 5 to less than 8 weeks for patients with a weight range of 40 kg to less than 80 kg.

[0039] As another example, the EID scheduling interval may be longer than 4 weeks but less than or equal to 6 weeks for patients with a weight range of less than 80 kg. As another example, the EID scheduling interval may be longer than 4 weeks but less than or equal to 6 weeks for patients with a weight range of 40 kg to less than 80 kg. In some embodiments, the EID scheduling interval may be longer than 4 weeks but less than 7 weeks for patients with a weight range of less than 80 kg. In some embodiments, the EID scheduling interval may be longer than 4 weeks but less than 7 weeks for patients with a weight range of 40 kg to less than 80 kg. In some embodiments, the EID scheduling interval may be longer than 4 weeks but less than 8 weeks for patients with a weight range of less than 80 kg. In some embodiments, the EID scheduling interval may be longer than 4 weeks but less than 8 weeks for patients with a weight range of 40 kg to less than 80 kg.

[0040] As another example, the EID scheduling interval may be at least 5 to 8 weeks for patients with a weight range of less than 80 kg. As yet another example, the EID scheduling interval may be at least 5 to 8 weeks for patients with a weight range of 40 kg to less than 80 kg. In some embodiments, the EID scheduling interval may be at least 5 to less than 9 weeks for patients with a weight range of less than 80 kg. In some embodiments, the EID scheduling interval may be at least 5 to less than 9 weeks for patients with a weight range of 40 kg to less than 80 kg.

[0041] As another example, the EID scheduling interval may be longer than 4 weeks but no more than 8 weeks for patients with a weight range of less than 80 kg. As yet another example, the EID scheduling interval may be longer than 4 weeks but no more than 8 weeks for patients with a weight range of 40 kg to less than 80 kg. In some embodiments, the EID scheduling interval may be longer than 4 weeks but no more than 9 weeks for patients with a weight range of less than 80 kg. In some embodiments, the EID scheduling interval may be longer than 4 weeks but no more than 9 weeks for patients with a weight range of 40 kg to less than 80 kg.

[0042] As another example, the EID scheduling interval may be longer than 4 weeks but no more than 9 weeks for patients with a weight range of less than 80 kg. As yet another example, the EID scheduling interval may be longer than 4 weeks but no more than 9 weeks for patients with a weight range of 40 kg to less than 80 kg. In some embodiments, the EID scheduling interval may be longer than 4 weeks but no more than 10 weeks for patients with a weight range of less than 80 kg. In some embodiments, the EID scheduling interval may be longer than 4 weeks but no more than 10 weeks for patients with a weight range of 40 kg to less than 80 kg.

[0043] In some embodiments, the patient weighs less than 120 kg. In some embodiments, the patient weighs between 40 kg and less than 120 kg. In some embodiments, the patient weighs less than 100 kg. In some embodiments, the patient weighs between 40 kg and less than 100 kg. In some embodiments, the patient weighs less than 80 kg. In some embodiments, the patient weighs between 40 kg and less than 80 kg. In some embodiments, the patient weighs less than 60 kg. In some embodiments, the patient weighs between 40 kg and less than 60 kg.

[0044] In some embodiments, the EID scheduling interval is selected to maintain mean trough α4β1-integrin receptor saturation of more than 60% (or more than 50, 55%, 65%, or 70%), or at least about 60% (or at least about 50%, 55%, 65%, or 70%), during the EID administration period in the patient population requiring natalizumab treatment. In some cases, the EID scheduling interval that maintains the reference mean trough α4β1-integrin receptor saturation of more than 50%, 55%, 60%, 65%, or 70%, or at least about 50%, 55%, 60%, 65%, or 70%, during the EID administration period in the patient population requiring natalizumab treatment is an EID schedule having an interval of more than 4 weeks and no more than 12 weeks. In some cases, during the EID administration period in a patient population requiring natalizumab treatment, the EID schedule intervals that maintain reference mean trough α4β1-integrin receptor saturation are EID schedules with intervals of at least 5 weeks, more than 4 weeks but less than 12 weeks, more than 4 weeks but 12 weeks or less, at least 5 weeks to 12 weeks or less, or at least 5 weeks to 12 weeks or less.

[0045] In some cases, the EID schedule intervals that maintain reference mean trough α4β1-integrin receptor saturation during the EID administration period in a patient population requiring natalizumab treatment are: longer than 4 weeks but less than 10 weeks, longer than 4 weeks but 10 weeks or less, at least 5 weeks to less than 10 weeks, at least 5 weeks to 10 weeks or less, longer than 4 weeks but less than 8 weeks, longer than 4 weeks but 8 weeks or less, at least 5 weeks to less than 8 weeks, at least 5 weeks to 8 weeks or less, at least 5 weeks to 7 weeks or less, at least 5 weeks to 6 weeks or less, or an EID schedule with an interval of 6 weeks.

[0046] In some cases, the EID schedule intervals that maintain reference mean trough α4β1-integrin receptor saturation during the EID administration period in a patient population requiring natalizumab treatment are EID schedules with intervals of more than 4 weeks but less than 7 weeks, more than 4 weeks but 7 weeks or less, at least 5 weeks to less than 7 weeks, at least 5 weeks to 7 weeks or less, more than 4 weeks but less than 6 weeks, more than 4 weeks but 6 weeks or less, at least 5 weeks to less than 6 weeks, or at least 5 weeks to 6 weeks or less.

[0047] In some cases, during the EID administration period in a patient population requiring natalizumab treatment, an EID schedule that maintains reference mean trough α4β1-integrin receptor saturation is an EID schedule with intervals of at least 4 weeks to less than 10 weeks, or at least 5 weeks to less than 10 weeks, where this patient population has a weight range of less than 60 kg (e.g., 40-59 kg). In some cases, during the EID administration period in a patient population requiring natalizumab treatment, an EID schedule that maintains reference mean trough α4β1-integrin receptor saturation is an EID schedule with intervals of at least 5 weeks to less than 8 weeks, or at least 5 weeks to 7 weeks or less, where this patient population has a weight range of less than 60 kg (e.g., 40-59 kg).

[0048] In some cases, during the EID administration period in a patient population requiring natalizumab treatment, an EID schedule that maintains reference mean trough α4β1-integrin receptor saturation is an EID schedule with intervals of more than 4 weeks but less than 8 weeks, or at least 5 weeks but less than 8 weeks, where this patient population has a weight range of less than 80 kg (e.g., 40-79 kg). In some cases, during the EID administration period in a patient population requiring natalizumab treatment, an EID schedule that maintains reference mean trough α4β1-integrin receptor saturation is an EID schedule with intervals of more than 4 weeks but less than or equal to 8 weeks, or at least 5 weeks but less than or equal to 8 weeks, where this patient population has a weight range of less than 80 kg (e.g., 40-79 kg).

[0049] In some cases, during the EID administration period in a patient population requiring natalizumab treatment, an EID schedule that maintains reference mean trough α4β1-integrin receptor saturation is an EID schedule with intervals of more than 4 weeks but less than 7 weeks, or at least 5 weeks to less than 7 weeks, where this patient population has a weight range of less than 80 kg (e.g., 40-79 kg).

[0050] In some cases, during the EID administration period in a patient population requiring natalizumab treatment, an EID schedule that maintains reference mean trough α4β1-integrin receptor saturation is an EID schedule with intervals of more than 4 weeks but less than or equal to 6 weeks, or at least 5 to 6 weeks, where this patient population has a weight range of less than 80 kg (e.g., 40 to 79 kg).

[0051] In some cases, an EID schedule that maintains more than 60% or at least approximately 60% of the reference mean trough α4β1-integrin receptor saturation during the EID administration period in a patient population requiring natalizumab treatment is an EID schedule with intervals of more than 4 weeks but less than 7 weeks, or at least 5 weeks to less than 7 weeks, where this patient population has a weight range of less than 100 kg (e.g., 40-100 kg). In some cases, an EID schedule that maintains more than 60% or at least approximately 60% of the reference mean trough α4β1-integrin receptor saturation during the EID administration period in a patient population requiring natalizumab treatment is an EID schedule with intervals of more than 4 weeks but less than or equal to 6 weeks, or at least 5 weeks to less than or equal to 6 weeks, where this patient population has a weight range of less than 100 kg (e.g., 40-100 kg). In some cases, an EID schedule that maintains more than 60% or at least about 60% mean trough α4β1-integrin receptor saturation during the EID administration period in a patient population requiring natalizumab treatment is an EID schedule with intervals of more than 4 weeks but less than or equal to 5 weeks, or with intervals of about 5 weeks, where the patient population has a weight range of less than 100 kg (e.g., 40-100 kg).

[0052] In some cases, an EID schedule that maintains more than 50% or at least approximately 50% mean trough α4β1-integrin receptor saturation during the EID administration period in a patient population requiring natalizumab treatment is an EID schedule with intervals of more than 4 weeks but less than or equal to 6 weeks, or at least 5 to 6 weeks, where this patient population has a weight range of less than 120 kg (e.g., 40-120 kg). In some cases, an EID schedule that maintains more than 60% or at least approximately 60% mean trough α4β1-integrin receptor saturation during the EID administration period in a patient population requiring natalizumab treatment is an EID schedule with intervals of more than 4 weeks but less than or equal to 5 weeks, or at least 5 weeks, where this patient population has a weight range of less than 120 kg (e.g., 40-120 kg).

[0053] As is understood, the standard FDA-approved dose is 300 mg. Therefore, in some embodiments, the SID dose, or the EID dose, and typically both the SID dose and the EID dose, are 300 mg. Thus, in some cases where the patient has a weight range of 40 kg to 79 kg, the dose may be 3.75 mg of natalizumab per kg of patient weight to 7.5 mg of natalizumab per kg of patient weight. Similarly, in some embodiments, the dose may be 3.75 mg of natalizumab per kg of patient weight to 7.5 mg of natalizumab per kg of patient weight. In some cases where the patient's weight range is 40 kg to 59 kg, the dose may be 5 mg of natalizumab per kg of patient weight to 7.5 mg of natalizumab per kg of patient weight. Similarly, in some embodiments, the dose may be 5 mg of natalizumab per kg of patient weight to 7.5 mg of natalizumab per kg of patient weight.

[0054] In some cases where the patient's weight range is 40 kg to 99 kg, the dose may be 3.03 mg of natalizumab per kg of patient weight to 7.5 mg of natalizumab per kg of patient weight. Similarly, in some embodiments, the dose may be 3.03 mg of natalizumab per kg of patient weight to 7.5 mg of natalizumab per kg of patient weight. In some cases where the patient's weight range is 40 kg to less than 120 kg, the dose may be 2.50 mg of natalizumab per kg of patient weight to 7.5 mg of natalizumab per kg of patient weight. Similarly, in some embodiments, the dose may be 2.50 mg of natalizumab per kg of patient weight to 7.5 mg of natalizumab per kg of patient weight.

[0055] In some embodiments, the EID schedule includes 15 doses or less over an 18-month period. In other embodiments, the EID schedule includes 10 doses or less over a 12-month period. In some embodiments, the EID schedule includes 10 doses or less per year over the duration of the infusion history.

[0056] In some embodiments, the EID schedule includes at least three doses of natalizumab, each dose administered on average every 5 to 12 weeks. For example, the EID schedule may include a single dose of natalizumab (starting on day 0), followed by doses every 5 weeks for at least 10 weeks or at least 15 weeks. In some embodiments, the EID schedule includes single doses of natalizumab every 6 weeks for at least 12 weeks or at least 18 weeks. In some embodiments, the EID schedule includes single doses of natalizumab every 7 weeks for at least 14 weeks or at least 21 weeks. In some embodiments, the EID schedule includes single doses of natalizumab every 8 weeks for at least 16 weeks or at least 24 weeks. In some embodiments, the EID schedule includes single doses of natalizumab every 9 weeks for at least 18 weeks or at least 27 weeks. In some embodiments, the EID schedule includes administration of a single dose of natalizumab every 10 weeks over at least 20 weeks or at least 30 weeks. In some embodiments, the EID schedule includes administration of a single dose of natalizumab every 11 weeks over at least 22 weeks or at least 33 weeks. In some embodiments, the EID schedule includes administration of a single dose of natalizumab every 11 weeks over at least 22 weeks or at least 33 weeks. In some embodiments, the EID schedule includes administration of a single dose of natalizumab every 12 weeks over at least 24 weeks or at least 36 weeks.

[0057] In some embodiments, the EID schedule is tracked (administered) for at least 6 months. In some embodiments, the EID schedule is tracked for at least 12 months (1 year). In some embodiments, the EID schedule is tracked for at least 18 months. In some embodiments, the EID schedule is tracked for at least 24 months (2 years). In some embodiments, the EID schedule is tracked for at least 30 months. In some embodiments, the EID schedule is tracked for at least 36 months (3 years).

[0058] In some embodiments, the EID schedule includes intravenous infusion of natalizumab 300 mg every 6 weeks (-2 / +5 days), for example, up to 72 weeks. In some embodiments, the SID schedule includes intravenous (IV) infusion of natalizumab 300 mg every 4 weeks (-2 / +5 days), for example, up to 72 weeks.

[0059] In some embodiments, the EID schedule includes a variable dosing schedule that alternates at least two different intervals. As a non-limiting example, the first dose of natalizumab may be administered on day 0, the second dose on week 5, the third dose on week 12 (7 weeks after the second dose), the fourth dose on week 17 (5 weeks after the third dose), the fifth dose on week 24 (7 weeks after the fourth dose), and so on, with alternating doses at weeks 5 and 7. As another non-limiting example, the first dose of natalizumab may be administered on day 0, the second dose on week 6, the third dose on week 14 (8 weeks after the second dose), the fourth dose on week 20 (6 weeks after the third dose), the fifth dose on week 28 (8 weeks after the fourth dose), and so on, with alternating doses at weeks 6 and 8. As another non-limiting example, the first dose of natalizumab may be administered on day 0, the second dose at week 7, the third dose at week 13 (6 weeks after the second dose), the fourth dose at week 20 (7 weeks after the third dose), the fifth dose at week 26 (6 weeks after the fourth dose), and so on, with doses at weeks 7 and 6 alternating.

[0060] As described herein, EID schedules are provided to enhance the safety of natalizumab therapy. In some embodiments, EID schedules are provided to enhance the safety of chronic natalizumab therapy. Compared to SID, safety may be enhanced by reducing the risk of adverse events. In exemplary embodiments, EID reduces the risk of PML. In some cases, EID reduces the risk of PML, the risk of inducing the production of anti-natalizumab antibodies, the risk of patient sensitization to natalizumab, or a combination thereof. In some examples, EID reduces the risk of loss of efficacy of natalizumab treatment due to the production of anti-idiotype antibodies against natalizumab in the patient.

[0061] In some embodiments, the risk of developing PML in subjects receiving natalizumab on the EID schedule described herein is reduced by at least 20% compared to the risk of developing PML in subjects receiving natalizumab therapy on a 4-week interval SID schedule. For example, the risk of developing PML in subjects receiving natalizumab on the EID schedule described herein is reduced by at least 30%, 40%, or 50% compared to the risk of developing PML in subjects receiving natalizumab therapy on a 4-week interval SID schedule.

[0062] In some embodiments, the risk of developing PML in subjects receiving natalizumab on the EID schedule described herein is reduced by at least 20% compared to the risk of developing PML in subjects receiving natalizumab therapy on the SID schedule, and the efficacy of natalizumab therapy is reduced by less than 10% compared to the efficacy of SID. For example, the risk of developing PML in subjects receiving natalizumab on the EID schedule described herein is reduced by at least 30%, 40%, or 50% compared to the risk of developing PML in subjects receiving natalizumab therapy on a 4-week interval SID schedule, and the efficacy of natalizumab therapy is reduced by less than 10% compared to the efficacy of SID.

[0063] In some embodiments, the risk of developing PML in subjects receiving natalizumab on an EID schedule with at least 5-week intervals is reduced by at least 20% compared to subjects receiving natalizumab therapy on a SID schedule with 4-week intervals. For example, the risk of developing PML in subjects receiving natalizumab on an EID schedule with at least 5-week intervals is reduced by at least 30%, 40%, or 50% compared to subjects receiving natalizumab therapy on a SID schedule with 4-week intervals.

[0064] The subjects provided herein are typically male or female human subjects (patients) who are receiving or scheduled to receive treatment with natalizumab for a particular condition. This condition may be an autoimmune condition or an inflammatory condition. Often, an autoimmune condition is considered an inflammatory condition, and vice versa; therefore, in some embodiments, the subject has both an autoimmune condition and / or an inflammatory condition. An autoimmune condition is a condition in which the subject's immune system attacks the subject's own cells / tissues. Non-limiting examples of autoimmune conditions include multiple sclerosis (MS) (e.g., relapsing-remitting MS, secondary progressive MS, and / or primary progressive MS), Crohn's disease, rheumatoid arthritis, lupus erythematosus, celiac disease, Sjögren's syndrome, polymyalgia rheumatica, ankylosing spondylitis, type 1 diabetes mellitus, alopecia areata, vasculitis, and temporal arteritis. Many of the aforementioned conditions are also inflammatory conditions. Accordingly, in some embodiments, the method of the present disclosure includes identifying subjects for natalizumab therapy in an EID schedule, or administering natalizumab therapy to subjects in an EID schedule at intervals of at least 5 weeks, wherein subjects are at high risk of PML and have an autoimmune condition. In some embodiments, the autoimmune condition is multiple sclerosis. In some embodiments, the autoimmune condition is Crohn's disease.

[0065] In some embodiments, the subjects have been diagnosed with epilepsy. Epilepsy is a central nervous system disorder (neuropathy) in which the activity of nerve cells in the brain is impaired, causing periods of seizures or abnormal behavior, agitation, and sometimes loss of consciousness. Therefore, in some embodiments, the method of the present disclosure includes identifying subjects for natalizumab therapy on an EID schedule, or administering natalizumab therapy to subjects on an EID schedule with intervals of more than 4 weeks (e.g., at least 5 weeks), where the subjects have epilepsy, have recently had a seizure, or have epilepsy and have recently had a seizure. In some embodiments, the subjects are at high risk of PML and have epilepsy, have recently had a seizure, or have epilepsy and have recently had a seizure.

[0066] In some embodiments, subjects had a prior medical history of immunosuppression. In some embodiments, subjects were treated with immunosuppressants prior to receiving natalizumab therapy in a 4-week interval SID schedule.

[0067] Subjects at high PML risk are those who are seropositive for anti-JCV antibodies. In some embodiments, high PML-risk subjects are those who have previously undergone immunosuppression and are seropositive for anti-JCV antibodies. In some embodiments, PML-risk subjects have an anti-JCV antibody index level greater than 1.5 (e.g., mean index level). In some embodiments, low PML-risk subjects have an anti-JCV antibody index level of 0.9 or less (e.g., mean index level). The anti-JC virus index value is calculated from a two-step serum / plasma ELISA antibody assay (STRATIFY JCV® antibody (indexed) and Reflex to Inhibition Assay); see, e.g., Lee, P. et al. J of Clin Virol, 2013;57(2):141-146 (incorporated herein by reference)). Antibody index levels, assays for evaluating index levels, and the use of such index levels and assays for determining PML risk are described, for example, in WO 2012 / 166971 and WO 2014 / 193804.

[0068] A subject may be considered at high risk of PML if they are tested for serological positivity of anti-JCV antibodies before initiating natalizumab therapy, or if they switch from a serologically negative anti-JCV antibody state to a serologically positive anti-JCV antibody state during natalizumab therapy. In some embodiments, a subject is considered at high risk of PML if they have an anti-JCV antibody index level greater than 1.5 before initiating natalizumab therapy, or if they switch from a low anti-JCV antibody index level of 0.9 or less to an anti-JCV antibody index level greater than 1.5 during natalizumab therapy. For example, a subject may be tested for the presence or absence of anti-JCV antibodies before initiating natalizumab therapy. If the results of this test indicate that the subject is at low risk of PML (serologically negative for anti-JCV antibodies, or an anti-JCV antibody index level of 0.9 or less), the subject may be identified as a candidate for natalizumab therapy on a 4-week interval SID schedule. During natalizumab therapy on the SID schedule, subjects may be retested for the presence of anti-JCV antibodies (e.g., monthly, every 2, 3, 4, 5, or 6 months, or annually). If, at the time of retesting, a subject changes from seronegative to seronegative for anti-JCV antibodies, or if the anti-JCV antibody index level rises from 0.9 or less to above 1.5, this subject may be identified as a candidate for natalizumab therapy on the EID schedule at intervals of at least 5 weeks.

[0069] In some embodiments, subjects receive SID natalizumab therapy for at least one year before switching to EID natalizumab therapy. For example, subjects may receive SID natalizumab therapy for at least 18 months, at least 2 years, at least 30 months, at least 3 years, at least 42 months, at least 4 years, at least 54 months, or at least 5 years before switching to EID natalizumab therapy. In such embodiments, subjects may be high-PML-risk subjects who had an anti-JCV antibody index level greater than 1.5 before initiating natalizumab therapy, or subjects may be high-PML-risk subjects who switched to an anti-JCV antibody index level greater than 1.5 at some point during SID natalizumab therapy (e.g., within the first, second, third, fourth, or fifth year of SID natalizumab therapy).

[0070] Furthermore, this specification also describes methods for extended interval dosing in subjects who have a risk based on a certain length of treatment. For example, if a subject has been treated with SID natalizumab therapy for at least 12 months, at least 18 months, at least 2 years, at least 30 months, at least 3 years, at least 42 months, at least 4 years, at least 54 months, or at least 5 years, and is thereby identified as suitable for one or more EID natalizumab therapies described herein, and / or has been treated with one or more of the EID natalizumab therapies described herein, they may be identified as having a risk based on a certain length of treatment.

[0071] The single dose of natalizumab for EID natalizumab therapy is typically 300 mg, and this single dose is typically administered intravenously over 1 hour.

[0072] While the aforementioned EID schedules have been described in relation to natalizumab therapy, it is understood that such EID schedules are likely to be suitable for use with other α4-integrin-binding antibodies that increase PML risk, particularly those that bind to the same epitope or compete for epitope binding with natalizumab, or those that inhibit lymphocyte transport to the brain. In embodiments, such antibody therapies may include a fixed or variable SID interval and an EID interval that is augmented relative to the SID interval, for example, extended by about 275% or less. In some embodiments, the EID interval may be extended by at least about 25%. In some embodiments, the EID interval may be extended by at least about 25% and about 275% or less, at least about 25% and about 250% or less, at least about 25% and about 200% or less, or at least about 25% and about 150% or less. [Examples]

[0073] Examples To assess the individual risk of progressive multifocal leukoencephalopathy (PML) during standard interval (SID) and extended interval (EID) administration of TYSABRI®, a large-scale analysis of patient data obtained from the Touch Database was performed, including all patients with known positive anti-JCV antibody serological status and known prior immunosuppressant use. The Touch Database included patient demographics, TYSABRI® administration information, anti-JCV antibody status, PML status, and prior treatment history with immunosuppressive therapy. Patients with a history of intervals between two consecutive infusions exceeding 12 weeks ("medication gap") or less than 3 weeks ("overdose") were excluded. Three analyses of patient data were performed using defined dose definitions for SID and EID, as shown in Table 1. The three planned analyses, as well as their respective EID and SID selection criteria, were developed and completed under blinded conditions for PML events.

[0074] statistical analysis Demographic and treatment history data for the entire survey population and each EID analysis cohort were summarized using descriptive statistics. For the three planned analyses, time to event (PML occurrence) analyses using Kaplan-Meier estimates of cumulative risk were performed for the EID and SID cohorts. Time to event occurrence was based on the time since the initiation of natalizumab treatment. Log-rank tests were performed to compare time to event occurrence between the EID and SID cohorts. The conditional probability of PML at each exposure epoch (defined as a series of 12 infusions) was derived for the EID and SID cohorts using a life table stratified by prior immunosuppressant use (data represent patients without prior use, as only 5% of patients had previously used immunosuppressants). The PML hazard ratio (HR) for the EID and SID cohorts was estimated using a time-varying covariate Cox regression model adjusted for age, sex, and calendar year at natalizumab treatment initiation, as well as prior immunosuppressant use (yes / no) as a covariate, and cumulative number of infusions as a time-varying covariate.

[0075] For each analysis, the PML HR estimate (EID vs. SID) and its 95% confidence interval (CI) from the Cox model were the primary basis for inference. Specifically, if the upper limit of the 95% CI for the HR was less than 1, the EID cohort was considered to have a lower risk of PML than the SID cohort. If the estimated HR point was ≥0·9 and ≤1·1, the EID and SID cohorts were considered to have similar risk. If the lower limit of the 95% CI for the HR was greater than 1, the EID cohort was considered to have a higher risk. At the time of specifying the analysis design, it was expected that a reduction in risk of ≥50% (hazard ratio ≤0.5) would be detected with approximately 85% power, based on the expected survey population size and the expected number of PML events, as defined by the inference rules above.

[0076] The statistical analysis plan was developed and finalized under conditions where PML events were not known. PML data from the Tysabri Global Safety Database was integrated with TOUCH after the analysis plan was completed. [Table 1]

[0077] Example 1 - Primary Analysis: PML cases were reduced in the EID-1 cohort compared to the SID-1 cohort. The primary analysis assessed the risk of PML associated with the last 18 months of recorded infusion history. The EID cohort was defined as follows: the total number of infusions was 15 or less in the last 18 months of treatment (a month is defined as 30 days). Patients with the defined dosing pattern in the last 18 months were included in the EID cohort. The SID cohort was defined as follows: the total number of infusions was 16 or more in the last 18 months of treatment (a month is defined as 30 days). Patients with the defined dosing pattern in the past 18 months were included in the SID cohort. The number of patients who tested positive for anti-JCV antibodies in the EID and SID cohorts is shown in Table 2. Patient demographics are shown in Table 3. [Table 2] [Table 3]

[0078] The total number of TYSABRI® infusions (Table 4) and the total duration of TYSABRI® treatment (Table 5) for the SID and EID cohorts were determined. The number of TYSABRI® infusions before (Table 6) and at / after (Table 7) the start of the EID / SID treatment regimen were also determined for the SID and EID cohorts. [Table 4] [Table 5] [Table 6] [Table 7]

[0079] Time to event (PML occurrence) analysis using Kaplan-Meier estimates of cumulative risk was performed on EID and SID cohorts stratified by prior use of immunosuppressants. Within each tier of prior use of immunosuppressants (yes / no), log-rank tests were performed to compare time to event between the EID and SID cohorts.

[0080] In both patients with prior immunosuppressant treatment and those without such prior treatment, the PML risk estimate per 1,000 patients was consistently lower in the EID cohort compared to the SID cohort throughout the course of treatment with TYSABRI® (Table 8). Table 8 shows the PML risk estimates per 1,000 anti-JCV antibody-positive patients grouped according to the dosing schedule described in this example. As described above, the Extended Interval Dosing (EID) cohort was defined as patients with a total of 15 or fewer infusions in the past 18 months (a month defined as 30 days). The Standard Interval Dosing (SID) cohort was defined as patients with a total of 16 or more infusions in the past 18 months (a month defined as 30 days). PML risk estimates were obtained for patients with prior immunosuppressant treatment (previous immunosuppression (IS)) and patients without prior immunosuppressant treatment (no previous IS). [Table 8]

[0081] The number of PML cases per patient was significantly lower in the EID cohort compared to the SID cohort over 72 months (Figure 1A) and 120 months (Figure 1D). In the EID cohort, the number of PML cases per patient was significantly lower compared to the SID cohort in patients with no prior immunosuppressive treatment (Figure 1B) and patients with prior immunosuppressive treatment (Figure 1C).

[0082] These results demonstrate that, when the EID regimen is defined as 15 or fewer injections in the past 18 months, and the SID regimen is defined as 16 or more injections in the past 18 months, patients treated with the EML regimen had a significantly lower number of PML cases compared to patients treated with the SID regimen.

[0083] Example 2 - Secondary Analysis: The number of PML cases was reduced in the EID-2 cohort compared to the SID-2 cohort. A secondary analysis evaluated the long-term effects of either EID in the infusion history of patients at risk of PML. The EID cohort was defined as follows: the total number of infusions was 10 or less in the last 365 days of treatment. Patients with the defined dosing pattern in the past 365 days were included in the EID cohort and received EID infusions for 6 consecutive months or longer. The SID cohort was defined as follows: the total number of infusions was 11 or more in the last 365 days of treatment. Patients with the defined dosing pattern in the past 365 days were included in the SID cohort and received SID infusions for 6 consecutive months or longer. The number of patients who tested positive for anti-JCV antibodies in the EID and SID cohorts is shown in Table 9. Patient demographics are shown in Table 10. [Table 9] [Table 10]

[0084] The total number of TYSABRI® infusions (Table 11) and the total duration of TYSABRI® treatment (Table 12) for the SID and EID cohorts were determined. The number of TYSABRI® infusions before (Table 13) and at / after (Table 14) the start of the EID / SID treatment regimen were also determined for the SID and EID cohorts. [Table 11] [Table 12] [Table 13] [Table 14]

[0085] We analyzed time to event (PML occurrence) using Kaplan-Meier estimates of cumulative risk for EID and SID cohorts stratified by prior immunosuppressant use. Within each tier (yes / no) of prior immunosuppressant use, we performed log-rank tests to compare time to event between the EID and SID cohorts.

[0086] For both patients with and without a history of immunosuppressant treatment, the estimated PML risk per 1,000 patients was consistently lower in the EID cohort compared to the SID cohort throughout the course of treatment with TYSABRI® (Table 15). As described above, Table 15 shows the estimated PML risk per 1,000 anti-JCV antibody-positive patients grouped according to the dosing schedule described in this example. The SID cohort was defined as patients who received 11 or more infusions within the past 365 days. The EID cohort was defined as patients who received 10 or fewer infusions within the past 365 days. PML risk estimates were obtained for patients who had previously received immunosuppressant treatment (Prior IS) and patients who had not previously received immunosuppressant treatment (No Prior IS). [Table 15]

[0087] Over 72 months (Figure 2A) and 120 months (Figure 2D), the number of PML cases per patient was significantly reduced in the EID cohort compared to the SID cohort. In the EID cohort, the number of PML cases per patient was significantly reduced compared to the SID cohort in patients with no prior immunosuppressive treatment (Figure 2B) and patients with prior immunosuppressive treatment (Figure 2C).

[0088] These results demonstrate that when the EID regime was defined as 10 or fewer infusions in the 365 days immediately preceding treatment, and the SID regime was defined as 11 or more infusions in the 365 days immediately preceding treatment, the number of PML cases was significantly reduced in patients treated with the EID regime compared to patients treated with the SID regime.

[0089] Example 3 - Third-order analysis: The number of PML cases was reduced in the EID-3 cohort compared to the SID-3 cohort. In the tertiary analysis, the impact of administration history, primarily consisting of EIDs, on PML risk was evaluated. The EID cohort was defined as follows: the average number of infusions per year was 10 or less throughout the entire treatment period. Patients with a defined administration pattern throughout the entire treatment period were included in the EID cohort. The SID cohort was defined as follows: the average number of infusions per year was greater than 10 throughout the entire treatment period. Patients with a defined administration pattern throughout the entire treatment period were included in the SID cohort. The number of patients who tested positive for anti-JCV antibodies in the EID and SID cohorts is shown in Table 16. Patient demographics are shown in Table 17. [Table 16] [Table 17]

[0090] The total number of TYSABRI® infusions (Table 18) and the total duration of TYSABRI® treatment (Table 19) for the SID and EID cohorts were determined. [Table 18] [Table 19]

[0091] We analyzed time to event (PML occurrence) using Kaplan-Meier estimates of cumulative risk for EID and SID cohorts stratified by prior immunosuppressant use. Within each tier (yes / no) of prior immunosuppressant use, we performed log-rank tests to compare time to event between the EID and SID cohorts.

[0092] For both patients with and without a history of immunosuppressant treatment, the estimated PML risk per 1,000 patients was consistently lower in the EID cohort compared to the SID cohort throughout the entire course of treatment with TYSABRI® (Table 20). As described above, Table 20 shows the estimated PML risk per 1,000 anti-JCV antibody-positive patients grouped according to the dosing schedule described in this example. The SID cohort was defined as patients receiving an average of 10 or fewer infusions per year. The EID cohort was defined as patients receiving an average of 10 or more infusions per year. PML risk estimates were obtained for patients previously treated with immunosuppressants (Prior IS) and patients who had not previously received immunosuppressant treatment (No Prior IS). [Table 20]

[0093] Over 72 months (Figure 3A) and 120 months (Figure 3B), the number of PML cases per patient was significantly reduced in the EID cohort compared to the SID cohort. In the EID cohort, the number of PML cases per patient was significantly reduced compared to the SID cohort in patients with no prior immunosuppressive treatment (Figure 3C) and patients with prior immunosuppressive treatment (Figure 3D).

[0094] These results demonstrate that when the EID regime is defined as 10 or fewer infusions in the 365 days immediately preceding treatment, and the SID regime is defined as 11 or more infusions in the 365 days immediately preceding treatment, the number of PML cases was significantly reduced in patients treated with the EID regime compared to patients treated with the SID regime.

[0095] Summary of results from primary, secondary, and tertiary analyses (Examples 1-3) Of the 90,038 patients enrolled in this study, 35,521 were anti-JCV antibody positive and eligible for inclusion (Figure 4). After applying pre-specified EID and SID selection criteria, the study population included 1,988 patients with EID and 13,132 with SID in the primary analysis, 3,331 patients with EID and 15,424 with SID in the secondary analysis, and 815 patients with EID and 23,168 with SID in the tertiary analysis. The most common reasons for patient exclusion were the presence of medication gaps or overdoses in treatment history (criteria applied to the primary, secondary, and tertiary analyses), as well as available medication data for less than 18 months (primary analysis only).

[0096] Baseline demographics for the EID and SID groups were well-balanced across all three analyses (Tables 3, 10, and 17). In all three analyses, EID patients received more natalizumab infusions and had a longer total duration of natalizumab treatment than SID patients. EID patients in the primary analysis had received a median (range) of 37 (1–117) infusions before initiating EID. In the secondary analysis (where each infusion was defined as either EID or SID), EID-2 patients had received a median (range) of 25 (1–121) infusions before initiating EID. Across all three analyses, the mean average daily intake (ADI) over the entire treatment period was 35.0–43.0 days for EID patients and 29.8–30.5 days for SID patients.

[0097] The Kaplan-Meier estimated cumulative risk of PML was significantly lower in EID than in SID (Figures 1D, 2D, and 3D). In the primary and secondary analyses, the cumulative risk appeared to separate at 24–36 months, with increased separation at later time points. Cox regression analysis also identified a significant reduction in PML risk with EID treatment in both the primary and secondary analyses (both p<0.001; Table 21). The covariate-adjusted HR in the primary analysis was 0.06 (95% CI, 0.01–0.22), corresponding to a 94% reduction in relative risk between EID-1° patients and SID-1° patients. In the secondary analysis, the covariate-adjusted HR was 0.12 (95% CI, 0.05–0.29), corresponding to an 88% reduction in relative risk between EID-2° patients and SID-2° patients. Since no PML cases were observed using EID in the tertiary analysis, the estimated risk reduction point was 100%, and the 95% confidence interval for the Cox regression model was unestimable. [Table 21]

[0098] Previous immunosuppressant use significantly increased the risk of PML. The covariate-adjusted hazard ratio (HR) was 2.92 (95% CI, 1.67–5.11; p<0·001) in the primary analysis and 2.90 (95% CI, 1.60–5.27; p=0·001) in the secondary analysis (Table 21). However, the significance of this observation is limited by the small number of patients using immunosuppressants (95 for EID-1° and 175 for EID-2°).

[0099] Example 4 In Examples 1-3 above, the SID was based on an average daily intake (ADI) of 3 weeks or more but less than 5 weeks, and the EID was based on an ADI of 5 weeks or more but 12 weeks or less. Next, two pre-specified sensitivity analyses were performed to evaluate the inclusion of PML cases that occurred before JCV antibody testing and to investigate alternative definitions for EID. First, PML cases that occurred before the collection of anti-JCV antibody test results via TOUCH were assumed to be anti-JCV antibody positive and were added to the three planned analyses above. In the second sensitivity analysis, alternative EID definitions of 13 or fewer infusions in the past 18 months and 9 or fewer infusions over any 12-month period were used and included in the primary and secondary EID analysis groups, respectively. Alternative selection criteria for the tertiary analysis were not tested.

[0100] The robustness of the three analyses was evaluated to determine the impact of the study design decisions on the results. In the first sensitivity analysis, the effect of excluding patients with unknown anti-JCV antibody status was examined by including PML cases that occurred before 2012, under the assumption that all were anti-JCV antibody positive. This added 1 EID and 67 SID PML cases to the primary analysis, 5 EID and 65 SID PML cases to the secondary analysis, and 0 EID and 71 SID PML cases to the tertiary analysis. Using the same population denominator as the first analysis (since anti-JCV antibody status is largely unknown in the pre-2012 population), the EID vs. SID HR was in the range of <0.01 to 0.09 in all three analyses (Table 22).

[0101] A second sensitivity analysis examined the effect of the number of EID doses required to include patients in the EID group by using alternative EID eligibility criteria. The risk of PML was significantly lower with EID than with SID, using alternative EID selection criteria of 13 or fewer infusions in the past 18 months in the primary analysis (HR, 0.10; 95% CI, 0.02-0.45) or 9 or fewer infusions in 12 months in the secondary analysis (HR, 0.01; 95% CI, <0.01-0.09) (Table 22). Alternative EID selection criteria were not examined in the tertiary analysis.

[0102] To address the potential impact of selection bias on the composition of the EID analysis cohort, two post-hoc analyses were performed. By including patients with medication gaps in three planned analyses of PML risk, the effect of excluding patients with medication gaps (intervals between two infusions longer than 12 weeks) was evaluated, and the resulting hazard ratios ranged from 0.08 to 0.16 (Table 22).

[0103] All patients included in this study tested positive for anti-JCV antibodies at least once. A second post-hoc analysis was performed to assess whether the duration of serological positivity for anti-JCV antibodies influenced the risk estimation. Longitudinal anti-JCV antibody status (conversion from negative to positive at a given time point) was incorporated as a time-varying covariate into the Cox regression model. The resulting HR (95% CI) estimates were 0.05 (0.11–0.18) in the primary analysis and 0.11 (0.04–0.26) in the secondary analysis (Table 22). This sensitivity analysis was not performed in the planned tertiary analysis.

[0104] EID was associated with a conditional reduction in the risk of PML in each consecutive epoch of natalizumab treatment for all three definitions of EID and SID (Table 23). Over the first four treatment epochs (48 infusions or less), only one case of PML was observed in the EID group (secondary analysis); no cases were observed in the primary and tertiary analyses. In the fifth and sixth epochs (49–72 infusions), the risk of PML was significantly lower with EID than with SID in all three analyses (Table 23).

[0105] Thirteen PML cases were identified among patients who met the primary and secondary EID selection criteria. One case met only the primary analysis criteria, ten cases met only the secondary analysis criteria, and two cases met the criteria for both analyses. There were no PML cases in the tertiary analysis. Of the 13 patients who were all included in the secondary analysis at the time of PML diagnosis, eight had switched from EID back to SID and had been in SID for more than 28 weeks immediately prior to PML diagnosis (Figure 5). PML patients with a history of EID had longer natalizumab treatment durations, more natalizumab infusions before initiating the EID regimen, and a mean total of natalizumab infusions was higher than in the overall EID cohort (Table 24). Prior use of immunosuppressants was also more common in EID PML cases than in the overall EID cohort (primary analysis: 33% vs. 5%, secondary analysis: 17% vs. 5%). Of the seven PML cases for which pre-PML anti-JCV antibody index values ​​were available, six had index values ​​greater than 1.5 (Figure 5).

[0106] Therefore, the key analytical results described in Examples 1–3 are robust to changes in the definition of the EID interval, study inclusion / exclusion criteria, and PML definition, and provide further evidence in the United States that natalizumab EID is associated with a statistically significant, clinically meaningful reduction in PML risk in JCV antibody-+ patients compared to natalizumab SID. [Table 22] CI = Confidence Interval. EID = Extended Dosage Interval. HR = Hazard Ratio. JCV = JC Virus. NA = Not Analyzed. PML = Progressive Multifocal Leukoencephalopathy. SID = Standard Dosage Interval. *PML cases that occurred before 2012 and were assumed to be positive for anti-JCV antibodies were added to the analysis population. This added 1 EID and 67 SID cases to the primary analysis, 5 EID and 65 SID cases to the secondary analysis, and 0 EID and 71 SID cases to the tertiary analysis. †The alternative definition of EID was 13 or fewer infusions in the past 18 months in the primary analysis, and 9 or fewer infusions over 12 months in the secondary analysis. The alternative definition for the tertiary analysis was not considered. Patients with a medication gap of more than 12 weeks between infusions were added to the sensitivity analysis cohort of PML cases before 2012. §Cox regression modeling of JCV status as a time-varying covariate, EID vs. SID. This model was not tested in the tertiary analysis. Since no PML cases occurred in the EID-3° group, ¶95% CI is unestimable. [Table 23] PML risk is expressed as the incidence per 1000 patients (number of PML cases per adjusted number of at-risk patients) in anti-JCV antibody-positive patients who had not previously used IS in the primary and secondary definitions. Patients who had previously used IS could not be analyzed due to insufficient patient numbers. The adjusted number of at-risk patients was 95 in the EID-1° group, 689 in the SID-1° group, 171 in the EID-2° group, and 747 in the SID-2° group. PML risk could not be calculated in the tertiary analysis of EID because no PML cases occurred in this analysis. See Figure 4 for the definitions of EID and SID in the primary, secondary, and tertiary analyses. EID = extended interval administration. IS = immunosuppressant. JCV = JC virus. PML = progressive multifocal leukoencephalopathy. SID = standard interval administration. * Data spanning more than six years is not provided. [Table 24] PML risk is shown as the incidence per 1000 patients (number of PML cases per adjusted number of at-risk patients) in anti-JCV antibody-positive patients who had not previously used IS in the primary and secondary definitions. Patients who had previously used IS could not be analyzed due to insufficient patient numbers. The adjusted number of at-risk patients was 95 in the EID-1° group, 689 in the SID-1° group, 171 in the EID-2° group, and 747 in the SID-2° group. PML risk could not be calculated in the tertiary analysis of EID because no PML cases occurred in this analysis. See Figure 4 for the definitions of EID and SID in the primary, secondary, and tertiary analyses. EID = extended interval administration. IS = immunosuppressant. JCV = JC virus. PML = progressive multifocal leukoencephalopathy. SID = standard interval administration. *Data exceeding 6 years are not shown.

[0107] Example 5 The primary objective of this study is to evaluate the efficacy of extended interval infusion (EID) of natalizumab (300 mg IV infusion) in subjects previously treated with standard interval infusion (SID) for at least 12 months, in relation to continued SID treatment.

[0108] The secondary objectives are to evaluate the additional recurrence-based clinical efficacy criteria for natalizumab SID for at least 12 months in relation to continuous SID treatment, the additional magnetic resonance imaging (MRI) lesion efficacy criteria for natalizumab SID for at least 12 months in relation to continuous SID treatment, and the safety of natalizumab SID for at least 12 months in relation to continuous SID treatment.

[0109] [Table A] [Table B-1] [Table B-2]

[0110] Important selection criteria: • Participants' ability to understand the purpose and risks of the study and to provide signed and dated informed consent and authorization for the use of their confidential health information in accordance with national and local participant privacy regulations. • Diagnosis of relapsing-remitting multiple sclerosis (RRMS) according to the McDonald criteria. Treatment with natalizumab as disease-modifying monotherapy for RRMS, consistent with approved medication regimens for a minimum of 12 months prior to randomization. Participants must have received at least 11 doses of natalizumab during the 12 months prior to randomization, without missing any doses three months prior to randomization. • Expanded Disability Status Scale (EDSS) ≤ 5.5 at the time of screening. • No relapses in the last 12 months prior to randomization, as determined by enrolling the researchers.

[0111] Important exclusion criteria: ·Primary and secondary progressive multiple sclerosis (MS). • MRI positive for Gd-enhancing lesions at screening. • Participants for whom MRI is contraindicated (e.g., those with a contraindicated pacemaker or other contraindicated implanted metal device, those suffering from or at risk of side effects from Gd, or those with medically unmanageable claustrophobia). A history of any clinically significant (as determined by the Principal Investigator) cardiovascular, endocrinology, hematology, hepatology, immunology, metabolism (including diabetes), urology, pulmonary, neurology (excluding RRMS), dermatology, psychiatry, nephrology, or any other major medical condition that, in the opinion of the Principal Investigator, would preclude participation in the clinical trial. • Presence of anti-natalizumab antibodies during screening.

[0112] Example 6 preface This report shows the following: a. Detailed retrospective analysis of EID vs. SID; b. Proposals for further examining the effectiveness and safety of EID in relation to SID from the perspective of reducing PML risk; and c. State-of-the-art PK / PD modeling that takes body weight and extended dosing intervals into consideration.

[0113] Data Overview a. Detailed retrospective analysis of EID vs. SID The recommended dose of natalizumab in the approved prescribing information is 300 mg intravenously over 1 hour every 4 weeks. The most significant adverse event affecting the benefit-risk assessment of natalizumab is the development of progressive multifocal leukoencephalopathy (PML). The risk of PML is increased by the presence of anti-John Cunningham virus (JCV) antibodies, prolonged treatment duration, and prior use of immunosuppressant (IS) therapy. The impact of alternative drug regimens on the risk of PML has been limited.

[0114] In the United States, only prescribers enrolled in the MS TYSABRI Outreach: United Commitment to Health (TOUCH) prescribing program may prescribe natalizumab for the treatment of MS. The TOUCH database stores all natalizumab infusion records, demographic information, previous use of IS therapy, and JCV antibody status (JCV antibody status available from February 2012 onwards), and may provide information on alternative dosing intervals. PML cases are covered by Biogen's TYSABRI Global Safety The data is stored in the Database (PML Database). This analysis was designed to evaluate the potential impact of extended interval dosing (EID) compared to standard interval dosing (SID) on PML risk through a retrospective analysis of the TOUCH Database and the PML Database.

[0115] Research purpose Main purpose - Comparison of PML risk between patients who received Tysabri with the current recommended SID based on the TOUCH database and patients who received EID during their treatment history. The purpose of this study is to investigate the impact of EID as a defined action plan for PML risks.

[0116] Secondary purpose - Comparison of PML risk between patients with overall exposure to Tysabri consistent with what is expected based on SID and patients with overall exposure consistent with what is expected from EID based on TOUCH database.

[0117] The objective is to investigate the impact of a reduction in overall exposure to Tysabri on the risk of PML.

[0118] methodology This analysis included PML cases from TOUCH Prescription Program days and up to June 1, 2017. The PML database data cutoff (DCO) was adjusted to align with exposure data as of June 1, 2017. Throughout the planning and finalization of the Statistical Analysis Plan (SAP), all researchers, both Biogen and non-Biogen, remained denial of their PML data. PML data was integrated with TOUCH Prescription Program data after the SAP was finalized.

[0119] Because the TOUCH database reflects real-world clinical practice, patient selection, and daily life considerations, the frequency of natalizumab administration varies considerably among patients. To determine the impact of EID on the risk of PML, we evaluated three definitions of EID and SID with different periods of relevant time. These three definitions of EID and SID were based on a monthly administration frequency of 0.83 times for at least 18 months. [Table 25-1] [Table 25-2]

[0120] For all definitions, the risk of PML in the EID and SID groups was estimated using life table methods and Kaplan-Meier estimations. The hazards for PML in the EID and SID groups were compared using Cox regression models adjusted for age, sex, prior use of IS therapy, calendar year at initiation, and number of infusions.

[0121] Target and sample size The analysis population included patients who had tested positive for anti-JCV antibodies at any given time.

[0122] To analyze the prior use of IS therapy, the following reported drug combinations were included in IS therapy: azathioprine, azathioprine or mercaptopurine or thioguanine, cyclophosphamide, methotrexate, mitoxantrone, mycophenolic acid, and novantrone.

[0123] Patients who experienced a medication gap exceeding 12 weeks (defined as an interval of more than 12 weeks between two consecutive infusions) or an overdose (defined as an interval of less than 3 weeks between two consecutive infusions) were excluded from the analysis.

[0124] As of June 1, 2017, the TOUCH database contained data for 90,038 patients.

[0125] After applying the inclusion and exclusion criteria of Example 4, the number of patients analyzed for each definition was as follows: Definition 1a: 1,988 EID patients and 13,132 SID patients; Definition 1b: 998 EID patients and 14,122 SID patients; Definition 2a: 3,331 EID patients and 15,424 SID patients; Definition 2b: 1,870 EID patients and 17,902 SID patients; and Definition 3a: 815 EID patients and 23,168 SID patients. Since no PML cases were reported for Definition 3a, Definition 3b was not analyzed, and therefore, it was not expected that any meaningful results would be observed for the more restrictive Definition 3b.

[0126] Of the 196 PML cases reported in the United States as of January 3, 2017, more than 90 occurred after the implementation of anti-JCV antibody status checks in the TOUCH information collection form, suggesting that these cases occurred within a known population with anti-JCV status.

[0127] Using the size of these potential analysis populations and the approximate number of PML events, the primary comparison was expected to have approximately 85% power to detect the reduction in the risk of PML, assuming that EID can reduce the risk by ≥50% (i.e., hazard ratio [HR] ≤ 0.5). If the results of the analysis in the planned DCO on June 1, 2017, were not conclusive based on the criteria described in the statistical methods, a new analysis would be performed when the number of patients in the arbitrarily defined EID group reached twice the size of the current DCO.

[0128] Variables and data sources The data sources for this analysis were the TOUCH and PML databases. This analysis included demographic and treatment history data (including age, sex, previous use of IS therapy, total duration of natalizumab treatment, and total number of natalizumab infusions), as well as PML incidence.

[0129] statistical methods Kaplan-Meier time to event analysis For each definition described in Table 25, time to event (PML occurrence) analysis using KM estimates of cumulative risk was performed for the EID and SID groups, stratified by prior use of IS treatment. Time to event analysis was based on the time from the start of natalizumab treatment, not the number of natalizumab infusions.

[0130] Within each tier (yes / no) of prior use of IS therapy, a log-rank test was performed to compare the time to event between the EID and SID groups. It should be noted that the analysis was intended solely to determine whether the risk of PML in patients who received natalizumab with an EID regimen at some point in their treatment history was reduced compared to patients who received natalizumab with a consistent SID regimen.

[0131] Since EID regimens are likely to be initiated after varying lengths of SID treatment periods and tend to have much more limited treatment periods, the analysis did not determine the time to event for EID regimens compared to SID regimens and did not evaluate the effect of the degree of SID exposure prior to EID on the risk of PML.

[0132] Cox regression time until event analysis For each definition described in Table 22, a time-to-event analysis using a Cox regression model was performed to compare the hazard of PML between the EID and SID groups, using age, sex, cumulative number of infusions, calendar year since initiation of natalizumab treatment, and prior use of IS therapy (yes / no) as covariates. The time to event analysis was based on the time since initiation of natalizumab treatment, not the number of natalizumab infusions. The estimates of HR (EID to SID) and their 95% confidence intervals (CIs) from the Cox regression model were the primary basis for inference for each definition of EID. Specifically, if the upper limit of the 95% CI for HR was less than 1, the EID group was considered to have a lower risk of PML than the SID group. If the point estimate of HR was between 0.9 and 1.1, the EID and SID groups were considered to have a similar risk of PML. If the lower limit of the 95% CI for HR was greater than 1, the EID group should have had a higher risk of PML than the SID group.

[0133] The proportional hazards assumption was checked for validity, and if there was a significant deviation from the assumption, analysis based on the log-rank test was considered the primary approach.

[0134] demographics Baseline demographic characteristics were well-balanced across the EID and SID groups for each EID definition. The majority of patients (approximately 68%) were female. The median age of patients at the time of the first infusion was approximately 43.0 years (range: 6 to 84 years). Approximately 5% of patients had previously received IS therapy. All patients were known to have tested positive for anti-JCV antibodies at some point during natalizumab treatment.

[0135] Baseline demographic characteristics were generally consistent with the main analysis population for patients with known PML or positive JCV antibodies, for patients with known PML or positive JCV antibodies (including those with treatment gaps), and for patients with only treatment gaps.

[0136] Natalizumab exposure For each EID definition, the median total duration of natalizumab treatment was longer in the EID group (43.0 to 63.0 months across all definitions [range: 3 to 131 months]) than in the SID group (25.0 to 45.0 months across all definitions [range: 1 to 131 months]). The median total number of natalizumab infusions was higher in the EID group (32.0 to 53.0 infusions across all definitions [range: 2 to 137 infusions]) than in the SID group (26.0 to 46.0 infusions across all definitions [range: 1 to 142 infusions]). The median number of natalizumab infusions before the start of the defined EID treatment period for patients in the EID group was 37.0 infusions (range: 1–117 infusions) and 40.0 infusions (range: 1–115 infusions) for definitions 1a and 1b, respectively, and 25.0 infusions (range: 1–121 infusions) and 30.0 infusions (range: 1–122 infusions) for definitions 2a and 2b, respectively. The results for definitions 2a and 2b indicate that the majority of patients had received natalizumab in the SID regimen for more than two years before switching to the EID regimen. The median number of natalizumab infusions before the start of the defined SID treatment period for patients in the SID group was 27.0 infusions (range: 0–121 infusions) for definitions 1a and 1b, and 1.0 infusions (range: 1–31 infusions) for definitions 2a and 2b, respectively. The median number of natalizumab infusions at or after the start of the defined EID or SID treatment period was lower in the EID group (12.0 to 17.0 infusions [range: 4–120 infusions] across definitions 1a, 1b, 2a, and 2b) than in the SID group (19.0 to 28.0 infusions [range: 6–141 infusions]). Definition 3a was defined based on the overall mean of exposure; therefore, the EID regimen was not defined. Therefore, the number of natalizumab infusions before or after the initiation of EID treatment could not be calculated. The mean duration of two natalizumab infusions was longer in the EID group (35.0 to 43.0 days) than in the SID group (29.8 to 30.5 days) for EID definitions 1a, 2a, and 3a.

[0137] Natalizumab exposure data for patients with known PML or JCV antibody positivity, for patients with known PML or JCV antibody positivity (including those with treatment gaps), and for patients with only treatment gaps were generally consistent with the primary analysis population. However, for definitions 1a and 2a, JCV antibody-positive patients, including those with known PML or treatment gaps, received fewer natalizumab infusions in total than the main analysis population (median 50.0 infusions [range: 11–132 infusions] and 51.0 infusions [range: 6–137 infusions], respectively (median 41.0 infusions [range: 2–132 infusions] and 45.0 infusions [range: 3–137 infusions], respectively). Furthermore, for definitions 1a and 2a, JCV antibody-positive patients, including those with known PML or treatment gaps, received fewer natalizumab infusions before the start of the defined EID treatment period (median 30.0 infusions [range: 0–117 infusions] and 19.0 infusions [range: 1–121 infusions], respectively, compared to the main analysis population (median 37.0 infusions [range: 1–117 infusions] and 25.0 infusions [range: 1–121 infusions], respectively). The same trend was observed for definitions 1a and 2a in patients with only treatment gaps. Note: In sensitivity analyses including patients with treatment gaps, exposure time was calculated from the first to the last dose; the gap period was not removed from the exposure time summary.

[0138] result Each EID group was associated with a clinically and statistically significantly lower risk of PML compared to the SID group of patients positive for anti-JCV antibodies.

[0139] Risk analysis of progressive multifocal leukoencephalopathy Using lifetables across all EID definitions, the risk of PML in the primary analysis population was lower in the EID group than in the SID group when IS therapy had not been used prior to EID therapy. The sample size of patients who had previously used IS therapy was insufficient for interpretation. While we do not wish to be bound by theory, we believe that patients classified as having prior use of IS therapy would show a similar reduction in PML risk as a result of EID administration.

[0140] For each definition of EID, sensitivity analyses evaluating the risk of PML in patients with known PML or JCV antibody positivity (including patients with treatment gaps) and in patients with only treatment gaps were generally consistent with the primary analysis population.

[0141] For each definition of EID, the KM analysis of time to PML showed that the risk of PML in patients in the EID group was lower than in the SID group of the primary analysis population (Figures 1D, 2D, 3D, and 6-7). For patients with known PML or who were JCV antibody positive, and for JCV antibody positive patients including those with known PML or who had received treatment, the KM analysis of time to PML was consistent with the primary analysis population.

[0142] Hazards of progressive multifocal leukoencephalopathy For each definition of EID, Cox regression models of time to PML, including cumulative number of doses as a time-varying covariate, showed that EID treatment was associated with a lower risk of PML than SID treatment, with HR values ​​ranging from 0.014 (95% CI 0.002~0.091; p<0.0001) (Definition 2b) to 0.122 (95% CI 0.051~0.291; p<0.0001) (Definition 2a). No PML cases were reported for Definition 3a.

[0143] The results for patients with known PML or JCV antibody positivity, patients with known PML or JCV antibody positivity (including those with treatment gaps), and patients with only treatment gaps were consistent with the results for the primary analysis population.

[0144] Similar trends were observed for the time to PML for each EID definition, and for the estimated parameters of the Cox regression model.

[0145] Discussion and Conclusion This analysis demonstrates that in patients positive for anti-JCV antibodies, natalizumab EID treatment is associated with a lower risk of PML than SID treatment. This result is consistent across all EID definitions evaluated.

[0146] The EID population consisted mainly of patients who switched to EID treatment more than two years after receiving SID treatment, with an average dosing interval of approximately 5–6 weeks. Therefore, the relative reduction in PML risk observed between EID and SID in these analyses is due to patients who were positive for anti-JCV antibodies after natalizumab exposure longer than two years.

[0147] There are numerous limitations and potential biases that must be considered when interpreting the results of these analyses.

[0148] The most significant limitation is the lack of preserved efficacy data. Therefore, the cost-benefit analysis of EID treatment compared to SID treatment cannot be evaluated using this dataset. Given the impact of EID treatment on PML risk observed in this analysis, the Marketing Authorization Holder (MAH) is interested in further investigating the efficacy of natalizumab EID treatment to better inform about the cost-benefit analysis of EID.

[0149] Furthermore, index values ​​are not available in the TOUCH database; therefore, it is unclear how the low risk associated with EID treatment interacts with the reduced risk of PML associated with low index values, and whether the lack of index information may be biased toward the observed low risk of PML in EID treatment compared to SID treatment. Since EID treatment is typically used in clinical practice to reduce the risk of PML, patients who received EID treatment may have higher index values ​​than patients who received SID treatment, which could introduce bias toward the treatment group. There is also potential bias in the patients included in each EID definition. Patients treated with EID had a higher total exposure to natalizumab on average than patients treated with SID, which appears to have introduced bias toward the treatment group. Since most patients who switched to EID had received SID for longer than two years, patients who received EID treatment were SID-treated patients who had received SID before switching to EID but did not develop PML, which could introduce selection bias; this would likely be biased toward the treatment group.

[0150] Furthermore, since the presence of anti-JCV antibodies increases the risk of PML, only patients with known positive anti-JCV antibody test results were included in the analysis population. The TOUCH database collected only data on JCV antibody status from the latter half of 2012 onward; however, it should be noted that PML patients may have been anti-JCV antibody positive before this time. In the sensitivity analysis, all PML patients were assumed to be anti-JCV antibody positive and were included in the analysis.

[0151] Given the robustness, consistency, and magnitude of the differences between EID-treated and SID-treated patients regarding PML risk, the potential biases described in this section are unlikely to significantly influence the conclusion that the risk of PML is lower with EID treatment than with SID treatment in patients at high risk of PML, such as those positive for anti-JCV antibodies.

[0152] Because the TOUCH prescribing program does not collect efficacy data, additional studies may be conducted to better inform whether the efficacy of natalizumab is maintained with EID treatment and to provide more accurate information about the benefits and drawbacks of EID.

[0153] The results of this analysis cannot be generalized because it is unclear whether the observed effect of EID treatment on the risk of PML is maintained in different patient populations (e.g., patients with different body weights and other patient populations where the risk of PML may be higher than in the US population).

[0154] b. Further methods to enhance the effectiveness and safety of EID compared to SID in terms of reducing PML risk; In light of the aforementioned results from a TOUCH analysis comparing patients treated with standard interval dosing (SID) with patients treated with extended interval dosing (EID) of 6 months or longer, we have developed a multi-stage approach to enhance the efficacy and safety of EID over SID. This approach is considered suitable for clinical validation in randomized, controlled, open-label, and evaluator-blinded clinical studies. This includes retrospective analyses of established databases through sponsored research agreements and / or MAH-led retrospective collaborations, as well as prospective randomized controlled studies.

[0155] Randomized, controlled, open-label, evaluator-blinded clinical trial The primary objective of this trial is to evaluate the efficacy of natalizumab EID at at least 12 months in SID in relation to ongoing SID, with the main objective of estimating ΔSID-EID with high accuracy, a narrow 95% CI, and sufficient power to detect small but clinically relevant differences.

[0156] A schematic diagram of this prospective study design is presented as Figure 8, along with the following research evaluation criteria.

[0157] Primary evaluation criteria: Number of N / NE T2 lesions at 48 weeks • Blinded central readings provide objective outcome indicators for recurrence when blinding is not feasible. N / NE T2 is a cumulative (more transient) indicator for Gd lesions. Secondary evaluation criteria: • Clinical outcomes: Time to first relapse, ARR, (weeks 48 and 72), and safety • MRI: Number of new or newly enlarged T2 lesions at weeks 24 and 72, number of new Gd+-enhancing lesions and new T1 low-intensity lesions at weeks 24, 48, and 72. Endpoints for PK, PD, and exploratory biomarkers: • α4-integrin saturation • Natalizumab concentration • Lymphocyte subset Research population: Important selection criteria • Ages 18-60, RMS, EDSS ≤ 5.5 • Stable with SID natalizumab for at least 12 months • Includes JCV- and JCV+ • Disease activity prior to natalizumab: by regional label • No relapses in the 12 months prior to randomization. Key Exclusion Criteria • Previous use of immunosuppressants • Gd+ lesions during MRI screening ·Primary and secondary progressive MS

[0158] This is a prospective, randomized, interventional, controlled, open-label, and evaluator-blinded phase 3b trial in patients with relapse-resistant measles syndrome (RRMS) who have been receiving natalizumab SID for at least 12 months without relapse in the past 12 months. Participants will be randomized to one of two arms to continue receiving natalizumab at either (1) 4-week intervals or (2) 6-week intervals.

[0159] Randomization is stratified by country / region, body weight (>90kg vs. ≤90kg), and duration of natalizumab exposure (>3 years vs. ≤3 years). All MRI scans are read at a central facility, and evaluators are not informed of their allocation.

[0160] Participants will be screened at regularly scheduled outpatient visits (±3 days) for natalizumab doses. If there is no apparent disease activity based on Gd+ enhanced lesions on MRI at screening and all other eligibility criteria are met, they will be enrolled and randomized at the next monthly outpatient visit. Participants will receive open-label natalizumab at their assigned frequency (±3 days) throughout the 72-week study period.

[0161] Research basis: The safety and efficacy of the currently recommended dose (300 mg of natalizumab administered intravenously (IV) every four weeks) have been well established in clinical trials and in real-world clinical practice.

[0162] Some physicians extend the dosing interval of natalizumab in patients positive for anti-JCV antibodies (e.g., 6 weeks). In a pre-specified retrospective analysis of anti-JCV antibody-positive patients treated with natalizumab in the US TOUCH (Tysabri® Outreach: United Commitment to Health) program (n=18,755), the risk of PML was compared between patients treated with standard interval dosing (SID) and those treated with extended interval dosing (EID) for at least 6 months (mean dosing interval of 300 mg was 5-6 weeks). The majority of patients had been treated with SID for at least one year before switching to EID (median of 25 SID infusions prior to the switch). The analysis demonstrated a clinically and statistically significant reduction in the risk of PML in patients treated with EID. Whether extending the dosing interval of natalizumab can improve patient benefit / risk in some embodiments will be established in prospective, randomized, controlled trials described herein.

[0163] This study will evaluate the efficacy, tolerability, and safety of switching to EID (e.g., 6-week interval) after at least 12 months of disease stability with SID (4-week interval).

[0164] This prospective study is designed to generate high-quality efficacy data aimed at detecting small, clinically relevant differences by accurately estimating the difference between SID and EID with a narrow 95% confidence interval and sufficient power. While this data generation process is time-consuming, it will ultimately provide a higher level of evidence than what is possible from PK / PD modeling and registry analysis alone.

[0165] This study will be conducted in the United States, Canada, Germany, Italy, the United Kingdom, Spain, France, the Netherlands, Belgium, Australia, and New Zealand. The first patients are expected to be enrolled in the first quarter of 2019, and final results are expected in the second quarter of 2021.

[0166] Research objectives and evaluation criteria: Primary objectives and evaluation criteria: The primary objectives of this study are to evaluate the efficacy of natalizumab EID in patients previously treated with natalizumab SID for at least 12 months, with the aim of estimating the difference between SID and EID with high precision at a narrow 95% CI in association with continued SID treatment, and to detect small but clinically relevant differences with adequate power.

[0167] The primary endpoint related to this goal is the number of new or newly expanding T2 high-intensity lesions over 48 weeks.

[0168] The secondary objectives and evaluation criteria are as follows: To evaluate additional relapse-based clinical efficacy indicators of natalizumab EID in patients previously treated with natalizumab SID for at least 12 months, in relation to continuous SID treatment.

[0169] To evaluate additional MRI lesion efficacy indicators of natalizumab EID in patients previously treated with natalizumab SID for at least 12 months in association with continuous SID treatment.

[0170] To evaluate the safety of natalizumab EID in patients who have previously been treated with natalizumab SID for at least 12 months, in relation to ongoing SID treatment.

[0171] The secondary outcome measures related to these objectives are as follows: - Time to first relapse (Relapse is determined by the Independent Neurology Evaluation Committee) - Annual recurrence rates at weeks 48 and 72 - Percentage of patients experiencing relapse at weeks 48 and 72 - Number of new or newly expanding T2 lesions at weeks 24 and 72 - Number of Gd+ enhancing lesions and T1 low-intensity lesions at weeks 24, 48, and 72 - Safety assessment of adverse events (AEs) and serious adverse events (SAEs)

[0172] The exploratory objectives and evaluation items are as follows: To evaluate additional clinical and MRI efficacy, safety, and tolerability indicators that may be important to clinicians when deciding whether to administer natalizumab EID to patients who have previously been treated with natalizumab SID for at least 12 months in connection with continued SID treatment. This allows for analysis of the optimal responders for EID switching in patients previously treated with natalizumab SID for at least 12 months, in order to evaluate pharmacokinetics (PK), pharmacodynamics (PD), biomarkers, and patient-reported outcomes (PRO).

[0173] The exploratory evaluation criteria for these objectives are as follows: Outcomes of exploratory clinical efficacy: - Expanded Disability Scale at weeks 48 and 72 Progression of the Status Scale (EDSS) (lasting for 3 months) - EDSS improvement at weeks 48 and 72 (lasted for 3 months) - 9-Hole Peg Test (9HPT) time, Timed 25-Foot Walk (T25FW) time, and Symbol Digit Modality Test (SDMT) scores at weeks 48 and 72. Outcomes in exploratory safety and tolerability: - Screening and anti-natalizumab antibodies at weeks 12, 24, 36, 48, 60, and 72 - Anti-JCV antibody status as assessed at baseline and at weeks 24, 48, and 72. Outcomes of exploratory MRI: Volume at 48 and 72 weeks for Gd+ enhancement, T2 high intensity, and non-enhancing T1 low intensity lesions - Percentage of changes in brain volume (PBVC) at weeks 48 and 72, exploratory PK, PD, Biomarkers and PRO outcomes: - Serum trough natalizumab concentration (Ctrough) - Trough α4 integrin saturation - Lymphocyte count by lymphocyte subsets including T cells, B cells, and NK cells (CD4, CD8, CD19, and CD56) - Additional serum, plasma, whole blood RNA, and PBMC samples will be collected and stored for potential future testing of exploratory markers related to natalizumab treatment response or MS disease biomarkers, at the sponsor's discretion. For example, exploratory biomarkers may include, but are not limited to, serum neurofilament light chains, soluble vascular cell adhesion molecule 1 (VCAM 1), and α4-integrin expression. -PRO: Treatment Satisfaction Questionnaire for Medication (TSQM), Neurology Quality of Life (Neuro-QoL) fatigue questionnaire, Multiple Sclerosis Impact Scale (MSIS-29), EuroQol 5-D scale (EQ-5D-5L), and overall clinical impression scale (physician and patient) (weeks 12, 24, 36, 48, 60, and 72).

[0174] The objectives and evaluation criteria for the exploratory CSF substudy are as follows: In cases where MS disease activity is absent, investigate whether EID leads to evidence of CNS lymphocyte activity. CSF will be collected from informed subjects at a number of selected sites equipped with lumbar puncture capabilities and stored for future potential testing of exploratory markers related to natalizumab treatment response or MS disease biomarkers, at the sponsor's discretion. Exploratory biomarkers may include, but are not limited to, natalizumab concentration, lymphocyte count, lymphocyte subset, neurofilament light levels, immunoglobulin index oligoclonal bands (OCBs), or other inflammatory markers.

[0175] Rationale for selecting dosage and schedule: The recommended dose of natalizumab is 300 mg intravenous (IV) infusion every four weeks. A pre-specified retrospective analysis (n=18755) of anti-JCV antibody-positive patients treated with natalizumab in the United States compared the risk of PML between patients treated with SID and those treated with EID (300 mg with a mean dosing interval of 5–6 weeks). The majority of patients had been treated with SID for at least one year before switching to EID. This analysis demonstrated a clinically and statistically significant reduction in the risk of PML in patients treated with EID. This study evaluates the effectiveness of switching to EID (e.g., a 6-week dosing interval) in relation to maintaining the recommended dose.

[0176] Duration of research participation: Each participant will take part in this study for 88 weeks, including a 4-week screening period, a 72-week randomization treatment period, and a 12-week follow-up period. Follow-up period: 12 weeks

[0177] Research location: Approximately 80 facilities are planned, with roughly 70% located in North America, 25% in Europe, and 5% in Australia.

[0178] Number of planned targets: Approximately 480 participants are expected to be enrolled. Participants will be randomized in a 1:1 ratio for either SID or EID treatment. Randomization is stratified by country / region, body weight (≤90kg vs. >90kg), and duration of natalizumab exposure (over 3 years vs. ≤3 years).

[0179] Determining the sample size: To detect an increase in the mean number of new or newly expanding T2 lesions over 48 weeks at an alpha level of 0.05 (bilateral), a sample size of 400 subjects (200 subjects per arm) yields the following: - Over 80% power to detect an increase from an average of 0.3 (expected efficacy of the SID administration arm in this population) to 0.5. - Over 90% detection power to detect an average increase from 0.3 to 0.6. Historical data on MS treatment, including a meta-analysis of the relationship between new or newly expanding T2 lesions and recurrence, suggest little to no clinical relevance, with a mean difference of less than 0.2 in new or newly expanding T2 lesions over 48 weeks. Approximately 480 participants will be enrolled, representing a dropout rate of approximately 17%.

[0180] Research group: Selection Criteria To be eligible to participate in this study, candidates must meet the following eligibility criteria at the time of randomization or at the time specified in the individual eligibility criteria listed: 1. The subject's ability to understand the purpose and risks of the study and to provide signed and dated informed consent and authorization for the use of their confidential health information in accordance with national and local privacy regulations. 2. Ages 18-55 at the time of informed consent (comprehensive). 3. RRMS Diagnosis Treatment with natalizumab consistent with approved medication regimens for a minimum of 12 months prior to randomization. Participants were required to have received at least 11 doses of natalizumab in the 12 months prior to randomization and to have not missed any doses in the 3 months prior to randomization. 4. EDSS score < 5.5 at the time of screening. 5. No relapses in the 12 months prior to randomization, as determined by the registered principal investigator. 6. All women of potential pregnancy must practice effective contraception during the study and for three months after the last dose of the study treatment.

[0181] Exclusion criteria Candidates will be excluded from study enrollment if any of the following exclusion criteria exist at the time of randomization or as identified by each of the listed criteria. 1. History of human immunodeficiency virus (HVM) infection. 2. A history of hepatitis C (testing for hepatitis C virus antibody [HCV Ab]) or hepatitis B virus (testing for hepatitis B surface antigen [HBsAg] and / or hepatitis B core antibody [HBcAb]). 3. Positive on MRI for Gd-enhanced lesions at screening. 4. Subjects for whom MRI is contraindicated (e.g., having a pacemaker or other implanted metal device for which it is contraindicated, suffering from side effects of Gd, or at risk thereof, or having medically unmanageable claustrophobia). 5. Any clinically significant (determined by the principal investigator of the clinical trial) history of heart, endocrine, blood, liver, immune, metabolic (including diabetes), urinary, pulmonary, neurological (excluding RRMS), dermatological, psychiatric, renal diseases, or other major diseases that, in the opinion of the principal investigator of the clinical trial, prevent participation in the clinical trial. 6. History of malignant diseases including solid tumors and hematological malignancies (excluding basal cell and squamous cell carcinomas of the skin that are considered to have been completely resected and cured). 7. History of transplantation or any history of rejection therapy. 8. History of severe allergic reactions or anaphylactic reactions, or known hypersensitivity to any antibody drug therapy. 9. Clinically significant infections (e.g., cellulitis, abscess, pneumonia, sepsis) within 30 days before screening, or PML or other opportunistic infections at any time. 10. Presence of anti-natalizumab antibodies at screening. 11. Any signs or symptoms suggesting any serious infection based on the history, physical examination, or clinical tests determined by the principal investigator of the clinical trial. Treatment history 12. Pretreatment with cladribine, mitoxantrone, vaccination of T cells or T cell receptors, cyclophosphamide, cyclosporine, azathioprine, methotrexate, or mycophenolate mofetil. 13. Previous treatment with any therapeutic monoclonal antibody other than natalizumab within 24 months before randomization. 14. Pretreatment with total lymphoid irradiation. 15. Pretreatment with IV immunoglobulin (IVIg), plasma exchange, or apheresis within 12 months before randomization. 16. Treatment with intravenous or oral corticosteroids (topical corticosteroids are acceptable) or related products within 3 months prior to randomization. Various kinds 17. The study includes women who are considering becoming pregnant during the study period, or women who are pregnant or currently breastfeeding. 18. A history of drug or alcohol abuse within two years prior to enrollment, as determined by the principal investigator. 19. Any current enrollment in any other research procedure or disease research. 20. Unable to comply with research requirements. 21. Any other unspecified reason, in the opinion of the principal investigator or Biogen, that makes the subject unsuitable for enrollment.

[0182] Re-screening criteria: Subjects who failed screening due to a transient infection may be rescreened once within 30 days.

[0183] Treatment group: SID group: Approximately 240 subjects receive natalizumab as an IV infusion of 300 mg every 4 weeks (28 ± 3 days). EID group: Approximately 240 patients will receive natalizumab as an IV infusion of 300 mg every 6 weeks (42 ± 3 days).

[0184] Clinic visit schedule: Participants are expected to make a total of 21 or fewer visits to the clinic during this study, including the screening and follow-up periods.

[0185] Definition of dose-limiting toxicity: The definition of dose-limiting toxicity does not apply.

[0186] Rescue and treatment options for individual subjects Emergency treatment will be ordered for the subject if one or more of the following conditions are met. - Compared to previous scans performed as part of this study, four or more novel or expanding T2 lesions of any size. - An increase of 1.5 or more on the EDSS compared to the previous assessment (confirmed at least 12 weeks after the initial increase). - Two new or recurrent clinical relapses involving neurological symptoms not associated with fever or infection, occurring within a minimum of 24 hours, and meeting one of the following criteria: 1) an increase of 1 or more grades on two or more function scales of the EDSS; or 2) an increase of 2 or more grades on one function scale of the EDSS; or 3) an increase of 1 or more on the EDSS if the previous EDSS was 5.5 or less, or an increase of 0.5 or more if the previous EDSS was 6 or higher (an increase of 1.5 or more on the EDSS if the previous EDSS was equal to 0), clinical relapse.

[0187] If a patient treated with natalizumab EID experiences any of the above conditions, the principal investigator may, at their discretion, return the patient to natalizumab SID as emergency treatment within four weeks of either the date of an MRI showing disease activity or confirmation of EDSS progression for at least three months. Patients receiving emergency treatment other than natalizumab SID will be excluded from the study.

[0188] For patients experiencing acute clinical relapse, high-dose corticosteroid treatment may be administered as per the local standard treatment for relapse (maximum 5 days).

[0189] Discontinue the procedure: The trial procedure must be permanently discontinued for any of the following reasons: - The subject becomes pregnant. The trial procedure must be immediately discontinued and the pregnancy should be reported. - The subject expresses persistent anti-natalizumab antibodies (two consecutive measurements). - The subject develops PML. - The subject withdraws their consent. - The subject experiences a medical emergency requiring the permanent discontinuation of the research procedure. - At the discretion of the principal investigator for medical reasons - At the discretion of the principal investigator or sponsor due to non-compliance.

[0190] Subjects who have discontinued the trial treatment may remain in the trial and continue the tests and evaluations required by the protocol. If a subject chooses to discontinue the study, the Early Termination Visit should be conducted as soon as possible, but within 4 weeks after the last administration of the study treatment. Additionally, all End-of-Study (EOS) evaluations need to be carried out at a separate EOS clinic visit 12 weeks (±3 days) after receiving the final dose of the trial treatment. The main reasons for discontinuing the trial treatment need to be recorded in the subject's electronic case report form.

[0191] Effectiveness Evaluation: MRI Effectiveness Evaluation - Number and volume of T2 hyperintense lesions - Number and volume of Gd+ enhancing lesions - Number and volume of T1 hypointense lesions - PBVC

[0192] Clinical Effectiveness Evaluation - Relapse (Clinical relapse is evaluated as defined by new or recurrent neurological symptoms not related to fever or infection for more than 24 hours) - Neurological examinations and EDSS - 9HPT, T25FW, SDMT - TSQM, Neuro-QoL fatigue, MSIS-29, EQ-5D-5L Safety Evaluation: Status of AE, SAE, anti-natalizumab antibodies, and anti-JCV antibodies. Concentration Evaluation of Trial Treatment: Natalizumab concentration in serum trough. Pharmacodynamic Parameters: - Trough α4-integrin saturation. - Lymphocyte counts by lymphocyte subsets including T cells, B cells, and NK cells (CD4, CD8, CD19, CD34, and CD56). - Serum, plasma, whole blood RNA, PBMC, CSF (optional), and DNA (optional) should be tested at the sponsor's discretion for future potential tests of exploratory markers related to natalizumab treatment response or MS disease biomarkers and collected and stored.

[0193] DNA / RNA / proteomics sample collection: Rationale: To support the selection of appropriate dose regimens that optimize patient benefit / risk, it may be important to develop potential predictors and / or pharmacodynamic markers of treatment-related responses to EID regimens. Optionally, collect and store samples for whole blood RNA expression and / or proteomics profiling of MS disease activity and / or natalizumab treatment response (trials conducted at the sponsor's discretion). DNA samples will be collected from informed subjects and, if necessary, identify genes that may influence the response to natalizumab or the course of MS disease. Participation in genetic research is voluntary for patients, and pharmacogenomic analysis is exploratory (trials should be conducted at the sponsor's discretion). Potentially, any heterogeneity in clinical response to treatment may be associated with patient genetic variation. However, there is currently no data suggesting that specific genetic polymorphisms are associated with the response to natalizumab.

[0194] Sample of laboratory evaluation: Duplicate samples are not retrieved; however, aliquots of the original samples are saved as backups in case the original samples are lost or cannot be evaluated.

[0195] Statistical statement and analysis plan: The primary endpoint, new or newly expanding T2 lesions at week 48, will be analyzed using a negative binomial regression model with treatment as the classification variable and body weight (≤90kg vs. >90kg), EDSS score, and lesion area as covariates.

[0196] The mean lesion ratio between SID and EID (EID / SID) is derived from a model with a 95% confidence interval (CI) and associated p-value. If the p-value (two-sided) is less than 0.05, the treatments may be considered different. The possibility of a doubling of the mean lesion count in the EID group compared to the SID group may be excluded if the upper limit of the 95% CI is less than 2. The proportion of patients with new or newly expanding T2 lesions is analyzed using a logistic regression model with the same covariates as above. New or newly expanding T2 lesions at other time points, as well as Gd+ lesions, are analyzed similarly. The primary secondary endpoint of recurrence is also analyzed using a negative binomial regression model. Time to event endpoints is analyzed using Cox regression models and Kaplan-Meier estimations. Performance trial outcomes and PD biomarkers are analyzed using a mixed model of repeated measures. The relationship between PK concentration and efficacy endpoints (MRI lesions and recurrence), and the relationship between PD biomarkers and efficacy endpoints, is evaluated using a negative binomial regression model or a logistic regression model. We will also evaluate the differences in treatment among subgroups defined by PK concentration categories and α-integrin saturation level categories.

[0197] The incidence of adverse events (AEs) during the randomized treatment period is presented in a table, categorized by treatment group, severity, and relationship to the study treatment. The tabular summary includes incidence rates by system organ class and priority item. AEs and SAEs leading to trial discontinuation are summarized by treatment group. Clinically relevant abnormalities in laboratory parameters are identified by treatment group.

[0198] Preliminary analysis: A preliminary futility analysis, based on the number of new or newly expanding T2 lesions at 6 months, will be conducted when 50% of participants have received randomized treatment for 6 months or more. The preliminary futility analysis is designed to ensure that if a clinically meaningful loss of efficacy occurs in the EID group, the study can be stopped early to prevent unnecessary risk to trial participants with uncontrolled MS disease activity as a result of a lack of potential efficacy of EID.

[0199] Clinical trial discontinuation rules: If a preliminary futility analysis shows a statistically significant worsening of efficacy in the EID group compared to the SID group, as measured by new or newly expanding T2 lesions, the study will be terminated. This study may be terminated at any time after notifying the principal investigator. The principal investigator will be notified if the study is suspended, completed, or terminated.

[0200] The end of the study: The end of the study is the last subject, the last hospital visit.

[0201] Pass / Fail Criteria: None c. Modern PK / PD modeling that takes body weight and extended dosing intervals into account. The data, modeling, and simulation results are shown below. The simulation results for Cavg, Ctrough, and integrin saturation (%) over one year with natalizumab treatment in the following dose regimens are shown in Figure 9: 300 mg every 4 weeks (Q4W), every 5 weeks (Q5W), every 6 weeks (Q6W), every 7 weeks (Q7W), every 8 weeks (Q8W), every 10 weeks (Q10W), and every 12 weeks (Q12W). Predictions are presented for each of the four weight groups (40-<60kg, 60-<80kg, 80-<100kg, and 100-<120kg). Mean serum natalizumab concentrations and mean integrin saturation (%) over a one-year treatment period (0-52 weeks) are plotted for all treatment and weight groups.

[0202] As shown, previously published PK-PD models (Muralidharan 2017) with clinical endpoints (Gd+ lesion count, ARR, etc.) were developed for Tysabri-naive individuals and designed to evaluate Q4W administration at various dose levels. Therefore, these models cannot be directly applied to simulate a situation where an individual has been on a 300 mg Q4W-labeled dosing regimen for some time before transitioning to different frequencies of dosing (e.g., Q6W or Q8W). While we do not intend to be bound by theory, we believe there is a clear PD delay in the system, such as a decrease in integrin saturation, and that Gd+ lesion recurrence did not occur for some time after discontinuation of standard treatment, despite a rapid decrease in PK concentrations. Such apparent delays were not considered in PK efficacy models because they were not significant when Tysabri-naive individuals were simulated. However, these apparent delays must be considered when modeling the efficacy of natalizumab in patients with stable transitions to Q4W and Q6W dosing.

[0203] This study provides results from an updated modeling approach that addresses this apparent delay, as well as subsequent simulations from the model. In summary, the updated simulation results show that, in terms of integrin saturation, high levels of efficacy are maintained across all body weights with Q4W and Q5W dosing. Efficacy begins to decline more significantly in the two higher body weight categories at Q6W and gradually deteriorates with less frequent dosing.

[0204] method Data for modeling Study 101MS205 (RESTORE) was a prospective, randomized trial in patients with relapsing-type multiple sclerosis (MS) who had received natalizumab treatment for at least 12 months without MS relapse prior to randomization. Patients who had received 300 mg of natalizumab IV for at least 12 months prior to enrollment were randomly assigned in a 1:1:2 ratio to receive natalizumab, placebo, or an alternative therapy (intramuscular interferon beta-1a, glatiramer acetate, or methylprednisolone). Randomization took place at week 0 (at which point all patients had received their last natalizumab infusion). At week 28, patients discontinued placebo or alternative therapy and resumed open-label natalizumab. In analyses performed to characterize the timing of PK and PD changes after natalizumab discontinuation in this study, the mean trough natalizumab concentration in patients whose natalizumab treatment was discontinued decreased rapidly from 38.4 μg / mL at 4 weeks post-discontinuation to 3.8 μg / mL at 12 weeks [Plavina 2017]. However, α4-integrin saturation levels decreased slowly from a mean 89.4% at 4 weeks to 31.3% at 12 weeks, and then plateaued at approximately 10%–15% from 16 weeks onward. In patients whose natalizumab treatment was discontinued, there were no Gd+ lesions meeting the rescue criteria (one lesion with a volume greater than 0.8 cm³ or two or more lesions of any size) on magnetic resonance imaging (MRI) at 4 or 8 weeks.

[0205] However, the proportion of patients with Gd+ lesions meeting MRI rescue criteria increased to 2.5% at week 12 and further to 41.8% at week 16. Clinical relapses in patients whose natalizumab treatment was discontinued also increased in frequency after week 12 [Fox2014]. RESTORE data suggest that in patients who remained stable for at least 12 months on natalizumab treatment, the decline in α4-integrin saturation levels following natalizumab discontinuation was delayed compared to drug concentration levels, and that recovery of disease activity appears to correspond to the rate of decline in saturation levels.

[0206] To assess the relationship, data on α4-integrin saturation levels; Gd+ lesions at weeks 4, 8, 12, and 16; and the occurrence of clinical relapse up to week 16 in the patient population that had been stable for at least 12 months prior to natalizumab treatment in the RESTORE trial were used for modeling. Since the majority of patients who discontinued natalizumab resumed natalizumab at week 16 after the return of disease activity [Fox 2014], data from week 16 onward were excluded from modeling.

[0207] It should be noted that the 101MS206 trial (REFINE) is a prospective, randomized trial to further evaluate various natalizumab dosing regimens in patients who have received natalizumab for at least 12 months with a standard dosing regimen without MS relapses. The regimens studied included 300 mg IV Q4W and Q12W regimens. However, since MRI scans, neurological examinations, and α4-integrin saturation level blood sampling were performed at 12-week intervals, the REFINE data were used as a validation dataset for simulation results of Q4W and Q12W dosing, rather than as part of a model building dataset.

[0208] Model 1: Probability of Gd+ lesion occurrence The data were fitted using a generalized estimating equation (GEE) model that included lesion occurrence (yes / no) at weeks 4, 8, 12, and 16 as a repeated measures correlated response variable, and α4-integrin saturation levels at the corresponding time points as an explanatory variable.

[0209] The mean response was modeled using a logit-link function with a work correlation matrix that is interchangeable between time points. Specifically, assuming that γij represents the Gd+ lesion state of patient i at the j-th visit, j=1, ..., 4, the model for the probability of lesion development μij is g(μij)=β0+xijβ1, where xij is the saturation level of patient i at the j-th visit, and the logit-link function g(μij)=log(μij / [1-μij]) with a binomial basis distribution. Predicted values ​​of μ (probability of lesion development) for a given saturation level were derived from the model using robust estimation of variance.

[0210] In patients who met the MRI rescue criteria, the response value at subsequent follow-up visits was assigned to "Y," regardless of the actual scan results.

[0211] Model 2: Mean number of Gd+ lesions A similar GEE model was constructed to evaluate the relationship between the number of lesions at weeks 4, 8, 12, and 16 and the corresponding α4-integrin saturation levels at those time points. A log link function with a negative binomial basis distribution was used in the model for the mean number of lesions. Inter-time interchangeable working correlation matrices were also considered.

[0212] The predicted value of μ (mean number of lesions) given a saturation level was derived from the model using robust estimation of variance.

[0213] For patients meeting the MRI salvage criteria, the number of lesions observed at salvage was used to attribute subsequent outpatient response values, regardless of the actual scan results.

[0214] Model 3: Probability of clinical recurrence The probability of clinical relapse was assessed using a similar GEE model, with the repeated measures response variable being the occurrence of relapse (yes / no) at weeks 0–4, 5–8, 9–12, and 13–16, and the explanatory variable being α4-integrin saturation levels at weeks 4, 8, 12, and 16. A logit-link function with a binomial basis distribution was used. Interchangeable working correlation matrices between time points were also assumed. Predicted values ​​of μ (probability of relapse) given saturation levels were derived from the model using robust estimates of the variance.

[0215] In patients who experienced a relapse, the response values ​​at all subsequent time intervals were attributed as "Y".

[0216] Trough α4-integrin saturation levels by drug regimen Trough α4-integrin saturation at week 52 for each of the following drug regimens (300 mg Q4W, Q5W, Q6W, Q7W, Q8W, Q10W, and Q12W) was pre-simulated using a PK-α4 integrin model in 10,000 patients per drug regimen group, for each weight category (40~<60kg, 60~<80kg, 80~<100kg, and 100~<120kg). The resulting distributions (Table 26 and...) were then simulated. Using Figure 10), random samples were drawn from the steady-state trough saturation levels of various simulated populations. [Table 26]

[0217] Simulation for efficacy based on dosage regimen The proportion of patients with Gd+ lesions, the average number of Gd+ lesions, and the cumulative probability of recurrence in a given patient population were simulated according to the following two-step process.

[0218] Step 1: For a given population of size N with a given weight distribution, a random sample of N patients was drawn from the trough α4-integrin saturation level distribution described above, based on medication regimen and body weight. A truncated normal distribution (censored at levels 0% and 100%) was assumed. Previous simulation results of trough α4-integrin saturation levels at week 52 were assumed to represent typical steady-state levels.

[0219] Step 2: For each simulated patient, the predicted probability or predicted mean number of lesions and the variance of the predicted values ​​were derived from each model (models 1, 2, and 3 above) based on the trough α4-integrin saturation level in step 1 above. Next, the binary response (yes / no) of lesion (or recurrence) occurrence or number of lesions for each simulated patient was randomly sampled from a binomial or negative binomial distribution using the predicted values ​​and variance.

[0220] The above steps were repeated 10,000 times (10,000 simulations) for each dose regimen, taking into account each patient population. The GEE [Zeger 1988 model was constructed using the SAS (version 9.4) GENMOD procedure. Random sampling for the simulations was performed using the SAS random number generating functions RANNOR, RANBIN, and RAND.

[0221] result Model 1 The estimated values ​​(± standard error [SE]) of the model parameters were as follows: β0 = -0.59 ± 0.28 and β1 = -0.09 ± 0.01 (p < 0.0001) for the logit response. The resulting approximation curves of the Gd+ lesion occurrence probability with 95% confidence intervals are shown in Figure 11. To show the distribution of α4-integrin saturation levels, the mean and 95% prediction intervals are also plotted in Figure 11 for administration regimens Q4W, Q6W, and Q12W.

[0222] These results indicate that the probability of lesion development is very low within the expected trough saturation range of the Q4W administration regimen, but sharply increases within the expected range of Q12W.

[0223] The mean trough expected saturation level for the Q6W dose regimen appears to be more volatile, but in the region with a lower probability of lesion development, compared to those of the Q4W and Q12W regimens.

[0224] Model 2 The estimated model parameters (±SE) are as follows: log response β0 = 1.22 ± 0.36 and β1 = -0.13 ± 0.02 (p < 0.0001). The approximation curve obtained as a result of the mean number of Gd+ lesions with a 95% confidence interval is shown in Figure 12.

[0225] Model 3 The estimated values ​​(±SE) for the model parameters are as follows: logit response β0 = -2.18 ± 0.31 and β1 = -0.02 ± 0.01 (p < 0.0001). The approximation curve obtained as a result of the recurrence probability with a 95% confidence interval is shown in Figure 13. The recurrence probability, in contrast to the lesion probability, slowly increased with decreasing saturation levels and remained above zero even at high saturation levels, suggesting that clinical recurrence may be a more complex manifestation of disease activity than the occurrence of MRI lesions.

[0226] Simulation of outcomes for dose regimens Q4W and Q12W in the REFINE study population. The 101MS206(REFINE) trial was a prospective, randomized trial evaluating various natalizumab dosing regimens in patients who had received natalizumab for at least 12 months with a standard dosing regimen and who had not experienced any MS relapses. REFINE study data from Q4W and Q12W of 300 mg IV were used as a validation dataset for simulation results from this model.

[0227] The sample size and weight distribution of the 300 mg IV Q4W and Q12W groups in the study formed the basis for simulating the proportion of patients with Gd+ lesions, the mean number of lesions, and the cumulative probability of recurrence in the study. The study populations of 51 and 45 patients were simulated 10,000 times with the Q4W and Q12W dosing regimens, respectively. Since more than 20% of patients in the IV Q12W group of the trial received emergency treatment after 24 weeks, comparisons between simulation results and actual observations were limited to data up to 24 weeks. Within the range of variation, the simulated probability of Gd+ lesion occurrence, the mean number of Gd+ lesions, and the cumulative probability of recurrence, using models constructed from RESTORE data, were similar to those observed in the REFINE study (Table 27). [Table 27]

[0228] Note that while the simulation results for the Q4W dosing regimen appear consistently lower than the actual observed results, all were within the 95% confidence interval of the observed results. Therefore, the REFINE trial cross-validates the models described herein.

[0229] Simulation of efficacy outcomes for the 300mg administration regimen at Q4W, Q5W, Q6W, Q7W, Q8W, Q10W, and Q12W (by body weight category). Tables 28–30 provide simulated outcomes for each dosing regimen and weight category, including the proportion of patients with Gd+ lesions, the mean number of Gd+ lesions, and the cumulative probability of relapse at week 48 in each population of 500 patients. In the simulated scenarios, the efficacy of natalizumab decreased with increasing dosing intervals, along with weight. However, the efficacy outcomes at Q5W and Q6W were similar to those with the Q4W dosing regimen. The loss of efficacy appears to accelerate from dosing interval Q8W onward. [Table 28] [Table 29] [Table 30]

[0230] conclusion A model characterizing the relationship between efficacy outcomes and α4-integrin saturation levels was developed using data from the 101MS205 trial (RESTORE). These models were then used to simulate the efficacy outcomes of the 101MS206 trial (REFINE) as validation. The simulated results were very similar to the actual observed results of REFINE. Next, the models were used to simulate the proportion of patients with Gd+ lesions, the mean number of Gd+ lesions, and the cumulative probability of relapse at week 48 for various dosing regimens, broken down by weight category. Q4W and Q5W dosing maintained high levels of efficacy across all weight categories. It began to decline more significantly in the two higher weight categories at Q6W and gradually worsened with less frequent dosing. The PK of Tysabri is characterized by a mean ± SD half-life of 16 ± 4 days. Therefore, stable trough concentrations are reached approximately 15–24 weeks after switching to extended dosing intervals.

[0231] Natalizumab PK may exhibit linear and nonlinear removal. The nonlinearity of PK can lead to changes in integrin binding, resulting in concentration imbalances and, in some cases, increased variability in α4-integrin saturation levels. In some embodiments, simulation results are interpreted taking this limitation of heterogeneous variability into account. Since the modeling was based on RESTORE data up to rescue (week 16), no patients experienced more than one relapsed episode; therefore, in some embodiments, the model may estimate only the cumulative probability of relapse, rather than the ARR.

[0232] Scientific considerations Analysis of the TOUCH and PML databases ultimately showed that in patients positive for anti-JCV antibodies, EID treatment was associated with a lower risk of PML than SID treatment.

[0233] Efficacy data may not be included. In some cases, the provided dataset does not include efficacy data, making it impossible to evaluate equivalent EID vs. SID. In some embodiments, for example, results from a recent analysis of TOUCH data combined with prospective studies described herein are generalizable to patients in the US population, including patients who have not been previously treated with natalizumab. In some embodiments, for example, results from a recent analysis of TOUCH data combined with prospective studies described herein are generalizable to patients in US and EU populations, including patients who have not been previously treated with natalizumab. In some embodiments, for example, results from a recent analysis of TOUCH data combined with prospective studies described herein are generalizable to patients requiring treatment with α4 integrin inhibitors, including patients who have not been previously treated with natalizumab.

[0234] The hazards for PML in both the EID and SID groups were compared using a Cox regression model adjusted for age, sex, prior use of IS therapy, calendar year at initiation, and number of infusions. These demographic characteristics were balanced between the two groups; however, while pharmacokinetic studies of natalizumab and modeling and simulation studies have shown that body weight may be a factor in efficacy, information on body weight and its distribution is not provided (see Part C). In some embodiments, MAH provides detailed subgroup analyses of the provided retrospective analyses of EID vs. SID with respect to body weight. Addressing body weight quartiles and various body weight cutoffs may better assess the PML risk of specific subgroups.

[0235] Proposals for further examining the effectiveness and safety of EID in relation to SID from the perspective of reducing PML risk; In general, clinical trials to further investigate whether the efficacy of natalizumab is maintained with EID treatment and to better inform about the benefits and drawbacks of EID in specific patient populations are approved. MAH offers a comprehensive proposal:

[0236] The PK of Tysabri is characterized by a mean ± SD half-life of 16 ± 4 days. Therefore, after switching to an extended dosing interval, stable trough concentrations are reached approximately 15–24 weeks later. Consequently, the primary clinical endpoint of the planned study should be shifted toward the end and set at 72 weeks.

[0237] As outlined in Part A, body weight is an efficacy factor and will be addressed in well-supported, well-planned clinical trials (Part B). However, the proposed 90 kg weight cutoff point is not fully supported due to the following considerations.

[0238] - The majority of MS patients are female; only a relatively small number of patients are expected to meet the body weight criteria of over 90 kg.

[0239] - Based on current modeling and simulation results, EID treatment (Q6W) may lower saturation levels of Ctrough and alpha-integrin in patients weighing 80 kg or more.

[0240] Therefore, the selection of 90 kg in the comparative analysis is considered too high and should be set to a lower value that is clinically and statistically justifiable. Furthermore, body weight should be included as a continuous variable in the supplementary analysis for body weight in order to better assess the clear impact of body weight on efficacy in the planned study.

[0241] Modern PK / PD modeling that considers body weight and extended dosing intervals. Conclusions based on the latest PK / PD models suggest that Q6W administration may be supported without significant loss of efficacy / potency, but moderate uncertainty remains.

[0242] In connection with updating the PK / PD modeling, three integrin saturation versus efficacy outcome models were established based solely on RESTORE data.

[0243] Using a generalized estimation equation, integrin saturation levels were compared to three efficacy parameters: the probability of lesion occurrence, mean number of lesions, and probability of recurrence, all measured by trough integrin saturation levels. In some patients, response values, such as the number of observed lesions, were attributed regardless of the actual scan results.

[0244] Despite the estimates ± standard errors of the two model parameters (β0, β1) for each of the three models, no further evaluation of these models is provided (no observed data is shown, no detailed modeling report is provided, there is no clear justification for the selection of data / models for model construction and validation, and there is no information regarding the influence and sensitivity of the assigned observations). The applicant is requested to provide more detailed information in order to better evaluate the validity and uncertainty of the models.

[0245] The established model was validated using data from the REFINE clinical trial, which was considered acceptable. Based on integrin saturation data (Q4W, Q12W) and efficacy data, the model-based predictions tended to underestimate efficacy outcomes compared to observed values.

[0246] A key point in model-based simulations is the Xij-Matrix, which reflects integrin saturation and therefore corresponds to the link between efficacy and PD parameters.

[0247] Further simulations of Ctrough and integrin saturation for various regimens (Q4W, Q5W, Q6W, ... Q12W) are based on the previous PK / PD model (Muralidharan et al. 2016) and are considered acceptable.

[0248] The applicant is required to provide RESTORE-related saturation data versus natalizumab serum concentrations in relation to observations gathered from all other relevant studies.

[0249] Further simulations of efficacy outcomes based on RESTORE modeling suggest that efficacy is maintained across all body weights with Q4W and Q5W administration. It begins to decline more significantly in two higher body weight categories (>80kg) at Q6W and gradually worsens with less frequent administration.

[0250] MAH is required to simulate PK(Ctrough) and integrin saturation throughout the study period, taking into account the level of natalizumab before switching to extended dosing. As previously reported, results should be provided categorized across various body weight ranges from 40 kg to 120 kg. These simulations may provide further insight into where to set the cutoff point for comparative body weight analyses in the planned trial (see Part B).

[0251] Appropriate primary body weight analysis during prospective clinical trials is considered necessary to provide evidence that 300 mg Q6W is acceptable for all subjects, or to determine if further pharmacokinetic adjustments are needed for certain subgroups.

[0252] In particular, simulation results regarding Cavg, Ctrough, and integrin saturation showed that MAH was related to the previous PSUR response. However, this only includes IV simulations; simulations of various regimens that gave SC were not shown. SC data and the application of SC mode were completely excluded from the MAH considerations. The SC program Q6W (adjusted for F) may be favorable for higher Ctrough / saturation at lower or similar Cavg at week 6. Further time-course plots after switching to extended dosing are not provided in this line.

[0253] Overall conclusion Part A (TOUCH): From the provided analysis, it can be concluded that each EID group is associated with a clinically and statistically significantly lower risk of PML compared to the SID group of patients positive for anti-JCV antibodies (and patients with no prior IS treatment). In some embodiments, stratified analyses by body weight are provided to better assess the risk in specific subgroups and to compare, contrast, or harmonize these results with the results of the planned clinical trial.

[0254] Part B (Phase 3b clinical trial): In general, clinical trials to further investigate whether the efficacy of natalizumab is maintained with EID treatment and to better inform about the benefits and drawbacks of EID in specific patient populations are approved. However, the MAH's proposal needs to be re-examined and modified in several respects. The definition and justification of margins may be considered in the EMA Scientific Advice procedure.

[0255] Part C (PK / PD analysis): The modeling results show a decrease in efficacy with increasing body weight and dosing interval duration. Further simulations of efficacy outcomes based on the RESTORE modeling suggest that efficacy is maintained across all body weights with Q4W and Q5W dosing. It begins to decline more significantly in two higher body weight categories (>80kg) at Q6W and gradually worsens with less frequent dosing. The model-based conclusions suggest that Q6W may be supportive for patients weighing less than 80kg, but moderate uncertainty remains. MAH is asked to perform several additional analyses and simulations to increase the evidence based on the model and to better assess the predictability of the quantitative model.

[0256] Impact on regulations Given the significant PML risk reduction effect of EID and the latest pk / pd modeling results (e.g., in patients with body weight <80kg) indicating that extended dosing intervals do not significantly impact efficacy, regulatory updates and communication of these new data are necessary. MAH is requested to make a proposal, which is deemed necessary because the final results of the proposed CT are expected in the second quarter of 2021, and waiting for the CT trial results is unacceptable based on current knowledge.

[0257] Part A (TOUCH): 1. MAH is requested to provide a detailed subgroup analysis of the retrospective EID vs. SID analysis for body weight. Not only body weight quartiles, but other clinically meaningful body weight cutoffs may also be addressed. The analysis from TOUCH should be updated when more data and body weight data are accumulated. This analysis should be used to further justify the cutoffs used for randomization in the planned Phase 3b trial.

[0258] Part B (Planned Phase 3b Clinical Trial): 2. The primary clinical endpoints of the planned study should be shifted toward the end and set at 72 weeks. 3. The stratification by body weight with a cutoff of 90 kg is considered suboptimal. Firstly, the balance of randomization is likely to be insufficient, as the subgroup >90 kg is expected to be quite small. Secondly, the justification for 90 kg as a cutoff is not clear from other clinical trials, including the TOUCH data. MAH is requested to reconsider the body weight cutoff in Phase 3b and provide a rationale for the cutoff. Furthermore, body weight should be included as a continuous variable in the supplemental analysis for body weight to better assess the clear impact of body weight on efficacy in the planned study. 4. Currently, primary statistical analyses are based solely on confidence intervals, and there are no clearly pre-specified success criteria. However, this should be based on non-inferiority testing. This includes pre-specifying and justifying a non-inferiority margin based on clinical and statistical evidence (see Guidelines on Non-Inferiority Margin Selection: EMEA / CPMP / EWP / 2158 / 99). This margin should preferably be defined as the difference in rates rather than proportions and should be based on data from the requested primary endpoint. 5. It should be noted that MAH does not necessarily exclude active studies, as a provisional test of the superiority of SID over EID may simultaneously and significantly reduce the effectiveness and non-inferiority of the endpoints, depending only on the width of the confidence interval and margin. Therefore, an appropriate futility analysis should be specified in advance. 6. MAHs should provide details on how mediating events (such as initiation of emergency medication, switching of treatment regimens due to AE or lack of effectiveness, discontinuation of treatment due to AE, discontinuation of treatment due to lack of effectiveness, etc.) are handled, as they are often mislabeled as missing data (comparison of estimates with ICH E9(R1)Draft Addendum; EMA / CHMP / ICH / 436221 / 2017), or are treated inappropriately in the analysis. MAHs should detail the planned estimates, i.e., what is being estimated, how these events are handled in the primary analysis, and which sensitivity or supplemental analyses are expected. 7. Currently, the stratification factors used in randomization and primary analysis are not well-adjusted. While the duration of exposure to natalizumab is used during randomization (among other factors), the EDSS is used instead in the primary analysis. The guidelines for adjusting baseline covariates in clinical trials (EMA / CHMP / 295050 / 2013) state that "stratification variables should normally be included as covariates or stratification variables in the primary analysis regardless of prognostic values ​​unless used solely for administrative reasons. Any inconsistencies in non-administrative covariates between stratification and adjustment in the primary analysis must be explained and justified." Therefore, MAH needs to be modified or justified as the applied stratification variable. Furthermore, it needs to be clarified how the EDSS is treated in the primary analysis model (i.e., as a linear covariate or categorical effect) if it is retained in the model. 8. The protocol should predict pre-planned subgroup analyses. These should include, in particular, subgroup analyses of body weight (using pre-specified cutoffs). To enable appropriate profit and loss considerations, both efficacy and safety results should be presented to these subgroups. 9. The definition and justification of study designs, including non-inferiority margins, should be considered in accordance with the EMA Scientific Advice procedure. These considerations should be appropriately reflected in both the statistical analysis methods and the sample size design.

[0259] Part C (PK / PD analysis): 10. Despite the estimates ± standard errors of the two model parameters (β0, β1) for each of the three models, no further evaluation of these models is provided (no observed data is shown, nor is there a detailed modeling report, no clear rationale for data / model selection for model construction and model validation, and no information on the influence and sensitivity of the assigned observations). The applicant is requested to report detailed information in accordance with the respective guidelines in order to better evaluate the validity and uncertainty of the models. 11. Further simulations of Ctrough and integrin saturation for various regimens (Q4W, Q5W, Q6W, ... Q12W) were based on a previous PK / PD model (Muralidharan et al. 2016) that was considered acceptable. The applicant is requested to present RESTORE-related saturation data versus serum natalizumab concentrations in relation to observations gathered from all other relevant studies. 12. MAH should simulate PK(Ctrough) and integrin saturation throughout the study period, taking into account the level of natalizumab before switching to extended dosing. As with previous reports, results should be presented categorized within a meaningful body weight range of 40 kg to 120 kg.

[0260] Regulatory consequences 13. Given the significant PML risk reduction effect of EID and the latest pk / pd modeling results (at least in patients with body weight <80 kg) indicating that extended dosage does not significantly affect efficacy, regulatory updates and communication of these new data are necessary. Therefore, MAH is requested to provide a proposed updated SmPC and a draft Dear Healthcare Provider Communication (DHPC) for review by PRAC. Changes to product information should be agreed upon with PRAC during the ongoing procedure LEG 066 and subsequently implemented as part of a subsequent Type IB variation.

[0261] Example 7: Reduction of the risk of progressive multifocal leukoencephalopathy by extended interval administration of natalizumab. summary the purpose Using a large dataset from the Tysabri Outreach: Unified Commitment to Health (TOUCH®) program, we compare the risk of progressive multifocal leukoencephalopathy (PML) with natalizumab extended interval administration versus standard interval administration in patients with multiple sclerosis.

[0262] method This retrospective cohort study included patients (N=35,521) who were positive for anti-JC virus antibodies as of June 1, 2017, with an interval between infusions longer than 3 weeks and less than 12 weeks in the TOUCH database. The impact of EID on PML risk was evaluated in three planned analyses. Cumulative PML risk for the EID and SID cohorts was estimated using the Kaplan-Meier method, stratified by prior immunosuppressant use. PML risk was analyzed by Cox regression adjusted for age, sex, prior immunosuppressant use, time since natalizumab initiation, and cumulative number of infusions.

[0263] result This study included 35,521 patients (Primary analysis: 1988 EIDs, 13,132 SIDs; Secondary analysis: 3331 EIDs, 15,424 SIDs; Tertiary analysis: 815 EIDs, 23,168 SIDs). The mean dosing intervals were 35.0–43.0 days and 29.8–30.5 days for the EID and SID cohorts, respectively. The hazard ratio (95% CI) for PML risk between EID and SID was 0.06 (0.01–0.22; p<0.001) in the primary analysis and 0.12 (0.05–0.29; p<0.001) in the secondary analysis. The relative risk reduction supporting EID in the primary and secondary analyses was 94% and 88%, respectively. There were no PML cases in the EID group in the tertiary analysis.

[0264] conclusion Natalizumab EID is associated with a clinically and statistically significantly lower risk of PML compared to SID. Further research is needed to evaluate the efficacy of EID.

[0265] preface Natalizumab, a monoclonal antibody against α4 integrin cell adhesion molecules, is being studied in randomized clinical trials. 1,2 and actual data 3,4As shown by, it is an effective treatment for relapsing multiple sclerosis (MS). The recommended treatment schedule (300 mg intravenous infusion every 4 weeks) was selected to provide saturation exceeding 80% of the mononuclear cell α4β1-integrin receptor for approximately 1 month after administration 5,6 For patients previously exposed to the JC virus (JCV), natalizumab treatment is associated with the risk of progressive multifocal leukoencephalopathy (PML) 7 Established risk factors for PML in anti-JCV antibody-positive patients include the level of anti-JCV antibodies in serum evaluated by the anti-JCV antibody index, the use of immunosuppressive therapy before the start of natalizumab, and the duration of natalizumab treatment 8,9 .

[0266] In real-world medical practice, treatment discontinuation, treatment interruption, and deviation from the recommended treatment schedule are not uncommon. For the purpose of maintaining the effectiveness of natalizumab while reducing the risk of PML, several retrospective studies investigated the impact of an extended interval dosing (EID) schedule (longer infusion intervals than 4 weeks) 10、11 . These studies, despite being limited by non-randomized designs, small patient populations, and the definition of EID variables, suggest that switching patients to natalizumab EID after a period of standard interval dosing (SID) continues to be favorable. However, since PML is a rare event, these studies did not have sufficient statistical power to evaluate whether EID is associated with a reduced risk of PML compared to SID. Therefore, the safety of natalizumab EID with respect to the risk of PML is not fully known

[0267] The Tysabri Outreach: Unified Commitment to Health (TOUCH®) program is a risk evaluation and mitigation strategy mandated by the US Food and Drug Administration 7,12It is designed to inform healthcare providers and patients about PML and its known risk factors; to warn about the concomitant use of antitumor agents, immunosuppressants, or immunomodulators; and to monitor patients for the development of PML and other serious opportunistic infections during treatment. The TOUCH database stores all natalizumab infusion records, patient demographic information, previous immunosuppressive therapy, and anti-JCV antibody status data (since February 2012). This is the world's largest dataset that can provide safety information related to alternative dosing intervals for natalizumab.

[0268] method research design This retrospective cohort study included data collected through the TOUCH program as of June 1, 2017, and included all patients with a known positive anti-JCV antibody serostatism and a known history of prior immunosuppressant use. PML data from Biogen's Tysabri Global Safety Database up to June 1, 2017, were also included in this study. Patients with a history of any interval longer than 12 weeks ("medication gap") or less than 3 weeks ("overdose") between two consecutive infusions were excluded. Three planned analyses and their respective EID and SID selection criteria were developed and finalized under conditions where PML events were concealed.

[0269] Main research topics The aim of this study was to determine whether natalizumab EID is associated with a reduced risk of premature malnutrition (PML) compared to SID, using a large, real-world TOUCH dataset. Because there is a lack of precise understanding of how natalizumab causes PML, or how the administration schedule may affect PML risk, we used three designed analyses with different EID selection criteria to evaluate both the impact of EID on PML risk and its potential mechanisms.

[0270] Classification of evidence This study provides Class IV evidence that natalizumab EID is associated with a statistically and clinically significant reduction in PML risk compared to SID in patients with relapsing-remitting multiple sclerosis.

[0271] Data collection Patient data collected via TOUCH include demographic information, date and dose of each natalizumab infusion, date and results of anti-JCV antibody tests performed in the past 12 months (since 2012), and treatment with immunomodulatory / immunosuppressive therapy in the past 6 months. Records of PML cases are kept in a separate pharmacovigilance database (Tysabri Global Safety). It is stored and maintained in the Database.

[0272] Planned analysis and selection criteria The TOUCH dataset demonstrates considerable variability in natalizumab administration, both intentional and unintentional, in US clinical practice. Furthermore, the optimal EID infusion interval and treatment duration remain unclear. Therefore, this study planned three different analyses of EID versus SID. In each analysis, different inclusion criteria (definitions) were employed for patients receiving EID and SID based on the number of doses received during a specified period, in order to test various hypotheses regarding the potential impact of EID on PML risk (Figure 14A-C). Patients may meet the inclusion criteria for more than one analysis.

[0273] In the primary analysis, the PML risk associated with the past 18 months of recorded injection history was assessed. Patients who received 15 or fewer injections in the past 18 months of treatment were included in the primary EID (EID-1°) analysis group; patients who received more than 15 injections in the past 18 months of treatment were included in the primary SID (SID-1°) analysis group.

[0274] In the secondary analysis, the impact of any long-term EID infusions on PML risk in patients' infusion history was evaluated. In this analysis, individual infusions were classified as either EIDs or SIDs. An EID infusion was defined as any infusion preceded by 10 or fewer infusions in the past 365 days. Patients who received such EID infusions consecutively for 6 months or more were included in the secondary EID (EID-2°) analysis group. Similarly, an SID infusion was defined as any infusion preceded by more than 10 infusions in the past 365 days, and patients who received such infusions consecutively for 6 months or more were included in the secondary SID (SID-2°) analysis group. Patients with a history of both EID-2° administration for 6 months or more and SID-2° administration for 6 months or more were included only in the EID-2° cohort. Patients with more than one EID-2° regimen were excluded to increase the rigor of the analysis.

[0275] In the tertiary analysis, the impact of administration history, primarily consisting of EIDs, on PML risk was evaluated. Patients who received 10 or fewer infusions per year throughout their treatment history were included in the tertiary EID (EID-3°) analysis group; patients who received more than 10 infusions per year were included in the tertiary SID (SID-3°) analysis group.

[0276] Two pre-specified sensitivity analyses were performed. First, PML cases occurring before 2012 (before the collection of anti-JCV antibody test results in TOUCH) were assumed to be anti-JCV antibody positive and were added to the three planned analyses mentioned above. In the second sensitivity analysis, surrogate EID definitions of 13 or fewer infusions in the past 18 months and 9 or fewer infusions in any 12-month period were used to include the primary and secondary EID analysis groups, respectively. The surrogate selection criteria for the tertiary analysis were not tested.

[0277] To monitor the safety of natalizumab in response to regulatory requirements, all analyses were performed on anonymized data collected through the TOUCH program with patient consent, and PML data collected through standard pharmacovigilance practices. No additional informed consent was required.

[0278] statistical analysis Demographic and treatment history data for the entire study population and each EID analysis cohort were summarized using descriptive statistics. For the three planned analyses, time to event (PML occurrence) analyses using Kaplan-Meier estimates of cumulative risk were performed for the EID and SID cohorts. Time to event occurrence was based on time after initiation of natalizumab treatment. Log-rank tests were performed to compare time to event occurrence between the EID and SID cohorts. The conditional probability of PML at each exposure epoch (defined as a series of 12 infusions) was derived for the EID and SID cohorts using a life table method stratified by prior immunosuppressant use. PML hazard ratios (HRs) for the EID and SID cohorts were estimated using a time-varying covariate Cox regression model adjusted for age, sex, and calendar year at initiation of natalizumab treatment, as well as prior immunosuppressant use (yes / no) as a covariate and cumulative number of infusions as a time-varying covariate.

[0279] For each analysis, PML HR estimates (EID vs. SID) and 95% confidence intervals (CIs) from the Cox model were the primary basis for inference. Specifically, if the upper limit of the 95% CI for HR was less than 1, the EID cohort was considered to have a lower risk of PML than the SID cohort. If the estimated HR point was between 0.9 and 1.1, the EID and SID cohorts were considered to have similar risk. If the lower limit of the 95% CI for HR was greater than 1, the EID cohort was considered to have a higher risk. At the time of specification of the analysis design, the expected population size of the trial and the expected number of PML events, as defined by the inference rules above, predicted that a risk reduction of 50% or more (i.e., HR ≤ 0.5) would be detected with approximately 85% power.

[0280] The statistical analysis plan was developed and finalized under blinded conditions for PML events. PML data from the Tysabri Global Safety Database was integrated with TOUCH after the analysis plan was completed.

[0281] result patient Of the 90,038 patients enrolled in TOUCH as of June 1, 2017, 35,521 were anti-JCV antibody positive and eligible for this study (Figure 15). After applying pre-specified EID and SID selection criteria, the study population included 1,988 EID patients and 13,132 SID patients in the primary analysis, 3,331 EID patients and 15,424 SID patients in the secondary analysis, and 815 EID patients and 23,168 SID patients in the tertiary analysis. The most common reasons for patient exclusion were medication gaps or overdoses in treatment history (primary, secondary, and tertiary analyses) and the presence of available medication data for less than 18 months (primary analysis only).

[0282] Baseline demographics for the EID and SID groups were balanced across all three analyses (Table 31). In all three analyses, EID patients received more natalizumab infusions and had a longer total duration of natalizumab treatment than SID patients. EID patients in the primary analysis had received a median (range) of 37 (1–117) infusions before initiating EID. In the secondary analysis (where each infusion was defined as either EID or SID), EID-2° patients had received a median (range) of 25 (1–121) infusions before initiating EID. Across all three analyses, the mean average daily intake (ADI) over the entire treatment period was 35.0–43.0 days for EID patients and 29.8–30.5 days for SID patients. [Table 31-1] [Table 31-2] Abbreviations: ADI = Mean Dosage Interval (overall treatment history); EID = Extended Dosage Interval; IS = Immunosuppressant; Q1 = First Quartile; Q3 = Third Quartile; SID = Standard Dosage Interval. For definitions of EID and SID in primary, secondary, and tertiary analyses, see Figure 14 and its explanation. a In less than 1% of patients in each group, information regarding the patient's sex was missing. bInformation regarding previous IS therapy was missing for 4% to 5% of patients in each group.

[0283] risk assessment The Kaplan-Meier estimated cumulative risk of PML was significantly lower in the EID group than in the SID group (Figures 16A-16C). In the primary and secondary analyses, cumulative risk appeared to separate at 24–36 months, and the separation increased at later time points. Cox regression analysis also confirmed a significant reduction in PML risk with EID treatment in both the primary and secondary analyses (both p<0.001; Table 32). The covariate-adjusted HR in the primary analysis was 0.06 (95% CI 0.01–0.22), corresponding to a 94% reduction in relative risk between EID-1° patients and SID-1° patients. In the secondary analysis, the covariate-adjusted HR was 0.12 (95% CI 0.05–0.29), corresponding to an 88% reduction in relative risk between EID-2° patients and SID-2° patients. In the third-order analysis, no PML cases were observed using EID, so the estimated risk reduction point was 100%, and the 95% CI of the Cox regression model was unestimable. [Table 32] Abbreviations: CI = Confidence Interval; EID = Extended Dosage Interval; HR = Hazard Ratio; IS = Immunosuppressant; PML = Progressive Multifocal Leukoencephalopathy; SID = Standard Dosage Interval. See Figure 14 and its explanation for the definitions of EID and SID in the primary, secondary, and tertiary analyses. Statistically significant results are shown in bold. a The model includes age, sex, previous use of IS, EID / SID group, and calendar year at the start of natalizumab treatment as covariates. Since no PML events occurred in the EID group in the tertiary analysis, modeling could not be performed in that group.

[0284] Previous use of immunosuppressants significantly increased the risk of PML. The covariate-adjusted hazard ratio (HR) was 2.92 (95% CI 1.67-5.11; p<0.001) in the primary analysis and 2.90 (95% CI 1.60-5.27; p=0.001) in the secondary analysis (Table 32). However, the significance of this observation is limited by the small number of patients using immunosuppressants (95 for EID-1° and 175 for EID-2°).

[0285] Sensitivity and post-hoc analysis The robustness of the three analyses was evaluated to determine the impact of the study design decisions on the results. In the first sensitivity analysis, the effect of excluding patients with unknown anti-JCV antibody status was examined by including PML cases that occurred before 2012, under the assumption that all were anti-JCV antibody positive. This added 1 EID and 67 SID PML cases to the primary analysis, 5 EID and 65 SID PML cases to the secondary analysis, and 0 EID and 71 SID PML cases to the tertiary analysis. Using the same population denominator as the planned analysis (since anti-JCV antibody status is largely unknown in the pre-2012 population), the HR for EID vs. SID ranged from <0.01 to 0.09 in all three analyses (Table 33). [Table 33] Abbreviations: CI = Confidence Interval; EID = Extended Dosage Interval; HR = Hazard Ratio; JCV = JC Virus; NA = Not Analyzed; PML = Progressive Multifocal Leukoencephalopathy; SID = Standard Dosage Interval. See Figure 14 and its explanation for the definitions of EID and SID in the primary, secondary, and tertiary analyses. a Cases of PML that occurred before 2012 and were presumed to be positive for anti-JCV antibodies were added to the analysis population. As a result, one case of EID and 67 cases of SID were added to the primary analysis, five cases of EID and 65 cases of SID were added to the secondary analysis, and zero cases of EID and 71 cases of SID were added to the tertiary analysis. bThe alternative EID definitions were 13 or fewer injections in the past 18 months for the primary analysis, and 9 or fewer injections in the past 12 months for the secondary analysis. No alternative definitions were considered for the tertiary analysis. c Patients with medication gaps of more than 12 weeks between infusions were added to the sensitivity analysis cohort of PML cases from before 2012.

[0286] In the second sensitivity analysis, the effect of the number of EID administrations required to be included in the EID group was examined using alternative eligibility criteria. The risk of PML was significantly lower with EID than with SID using the alternative EID selection criterion of 13 or fewer infusions in the past 18 months (HR 0.10; 95% CI 0.02-0.45) in the primary analysis, or 9 or fewer infusions over 12 months (HR 0.01; 95% CI < 0.01-0.09) in the secondary analysis (Table 33). Since no cases of EID-3° PML were observed, the alternative EID selection criterion was not examined in the tertiary analysis.

[0287] To address the potential impact of selection bias on the composition of the EID analysis cohort, two post-hoc analyses were performed. By including patients with medication gaps in three planned analyses of PML risk, the effect of excluding patients with medication gaps (interval between two infusions longer than 12 weeks) was evaluated, and the resulting hazard ratios ranged from 0.08 to 0.16 (Table 33).

[0288] All patients included in this study were tested for anti-JCV antibody positivity at least once. A second post-hoc analysis was performed to assess whether the duration of seropositivity for anti-JCV antibody affected risk estimation. Longitudinal anti-JCV antibody status (i.e., the change in antibody status from negative to positive at a given time point) was incorporated into the Cox regression model as a time-varying covariate. The resulting HR (95% CI) estimates were 0.05 (0.11–0.18) in the primary analysis and 0.11 (0.04–0.26) in the secondary analysis (Table 33). This sensitivity analysis was not performed in the tertiary analysis.

[0289] EID was associated with a conditional reduction in the risk of PML in each consecutive epoch of natalizumab treatment for all three definitions of EID and SID (Table 34). In the first four treatment epochs (48 infusions or less), only one case of PML was observed in the EID group (in the secondary analysis); no cases were observed in the primary and tertiary analyses. In the fifth and sixth epochs (49–72 infusions), the risk of PML in EID was significantly lower than in SID in all three analyses (Table 34). [Table 34] Abbreviations: EID = extended interval administration; IS = immunosuppressant; JCV = JC virus; PML = progressive multifocal leukoencephalopathy; SID = standard interval administration. PML risk is shown as the incidence per 1000 patients (number of PML cases per adjusted number of at-risk patients) in anti-JCV antibody-positive patients who had not previously used IS in the primary and secondary definitions. Patients who had previously used IS could not be analyzed due to insufficient patient numbers. The adjusted number of at-risk patients was 95 in the EID-1° group, 689 in the SID-1° group, 171 in the EID-2° group, and 747 in the SID-2° group. PML risk could not be calculated in the tertiary analysis of EID because no PML cases occurred in this analysis. See Figure 14 and its explanation for the definitions of EID and SID in the primary, secondary, and tertiary analyses. a Data spanning more than six years is not provided.

[0290] Cases of EID PML Thirteen PML cases were identified among patients who met the primary and secondary EID selection criteria. One case met only the primary analysis criteria, ten cases met only the secondary analysis criteria, and two cases met the criteria for both analyses. There were no PML cases in the tertiary analysis. Of the 13 patients who were all included in the secondary analysis at the time of PML diagnosis, eight had switched from EID back to SID and had been in SID for more than 28 weeks immediately prior to PML diagnosis (Figure 17). PML patients with a history of EID had longer natalizumab treatment durations, more natalizumab infusions before initiating the EID regimen, and a mean total of natalizumab infusions was higher than in the overall EID cohort (Table 35). Prior use of immunosuppressants was also more common in EID PML cases than in the overall EID cohort (primary analysis: 33% vs. 5%, secondary analysis: 17% vs. 5%). Of the seven PML cases for which pre-PML anti-JCV antibody index values ​​were available, six had an index value of >1.5 (Figure 17). [Table 35] Abbreviations: EID = extended interval administration; IS = immunosuppressant; Q1 = first quartile; Q3 = third quartile; SID = standard interval administration. See Figure 14 and its explanation for the definitions of EID and SID in the primary, secondary, and tertiary analyses. Patient characteristics in the tertiary analysis are not shown because no PML cases occurred in this analysis.

[0291] Consideration To address the issue of PML risk associated with EID, the inventors conducted a retrospective cohort study using patient data collected through the TOUCH program. This is the largest study to date on PML risk associated with natalizumab EID and also demonstrates how rigorous analysis of real-world data derived from the REMS program can address the issue of clinically meaningful risk reduction. Although PML is a rare event, the size of the TOUCH dataset provided sufficient power to produce robust and statistically significant results. The inventors evaluated the risk of PML in anti-JCV antibody-positive patients meeting any of the three inclusion criteria for natalizumab EID versus the risk in patients with SID using three different pre-selective analyses, examining a wide range of dosing patterns used in real-world clinical practice. In each of the three different analyses, the risk of PML with natalizumab EID was substantially reduced compared to SID.

[0292] The difference in dosing intervals between the EID and SID groups was relatively small (30–31 days for SID compared to 35–43 days for EID). While these values ​​are a combination of various treatments and dosing patterns, these results suggest that extending the dosing interval by just 1–2 weeks may significantly reduce the risk of PML. Historically, patients with any dosing interval of less than 3 weeks or more than 12 weeks were excluded from the planned analysis, and the third quartile (75th percentile) ADI range for the EID cohort was 37–45 days, so it is unlikely that the main conclusions of this study were affected by outliers at any end of the ADI range.

[0293] To assess the impact of the following two study design elements on the outcomes, pre-specified sensitivity analyses were performed: (1) including only patients with a known positive anti-JCV antibody status, and (2) the number of EID infusions required to be included in either the EID-1° or EID-2° group. Furthermore, a post-hoc sensitivity analysis was conducted to evaluate the impact of excluding patients with a history of dosing gaps (longer than 12 weeks between doses). The results of both the sensitivity and post-hoc analyses were comparable to the results of the three planned analyses, demonstrating robustness of the risk estimation and further reinforcing the main conclusion that natalizumab EIDs are associated with a lower PML risk than SID in patients at risk.

[0294] Potential selection bias arose in the composition of the EID cohort due to the likelihood that physicians were more likely to switch patients with prolonged JCV seropositivity to EID. When anti-JCV antibody positivity was described as a time-varying covariate in the second post-hoc analysis, the resulting HR and 95% CI were similar to those generated in the original pre-specified analysis, indicating that this potential bias did not affect the conclusions of the main study.

[0295] Identifying 13 PML cases among 5249 patients combined in the EID-1° and / or EID-2° groups indicates that these EID regimens are associated with a significantly lower risk of PML than SID, but the risk is not completely eliminated. The EID-3° group was relatively small (n=815), but no cases of PML were observed in a more rigorous tertiary analysis. Most of the EID PML cases described herein had multiple risk factors for PML, including a longer overall duration of natalizumab treatment, a longer duration of SID prior to switching to EID, and a higher likelihood of prior immunosuppressant use than patients in the corresponding overall EID cohort. Furthermore, some EID PML cases had reverted to SID before a PML diagnosis. Previously published case reports of PML in patients receiving natalizumab EID also showed that affected patients also had elevated PML risk factors, including a long-term SID preceding EID and an anti-JCV antibody index >1.5. 13 .

[0296] While further research is needed to understand the underlying biological mechanisms of the observed reduction in PML risk, it has been reported that a partial reversal of natalizumab's pharmacodynamic effects occurs 4–8 weeks after the last dose, including decreased receptor saturation, increased expression of soluble vascular cell adhesion molecules, and reduced natalizumab-induced peripheral lymphocyte enlargement. 14 This could potentially allow for the re-establishment of some immune surveillance in the central nervous system.

[0297] The conclusions of this study are limited by several inherent biases. EID patients received higher doses of natalizumab than SID patients, which may have introduced a selection bias favoring more PML cases in the EID cohort, given that natalizumab exposure is a known PML risk factor. Conversely, since most patients had received SID treatment for more than two years without developing PML before starting EID, the EID group may have included patients with a pre-existing reduced risk of PML, thereby introducing a selection bias that would result in fewer PML cases in the EID group. Also, anti-JCV antibody index data are not available for all patients with TOUCH; therefore, it is unclear whether the index values ​​differ between the EID and SID cohorts, and whether any such differences play a role in the risk reduction observed in this study. Since EID is used as an off-label strategy in clinical practice to reduce PML risk, anti-JCV antibody index values ​​may be higher in EID patients than in SID patients, as observed in retrospective studies of natalizumab EID. 11 If this is the case, the risk reduction observed in the EID cohort described herein may potentially be even greater in patient populations of EID and SID with the same distribution of anti-JCV antibody index values.

[0298] Finally, and most importantly, the TOUCH program did not collect information on treatment efficacy, and therefore could not evaluate the EID (Endostatic Dysfunction) benefit-loss profile compared to SID (Severity-Induced Illness). Several studies on patient outcomes after discontinuation of natalizumab have shown that MS disease activity is suppressed for at least 6 weeks, and possibly up to 12 weeks after the last dose. 15-18 Furthermore, two retrospective studies suggest that the effectiveness of natalizumab is not diminished by the EID regimen. 10、11 However, the results of the latter studies are limited by non-randomized designs, small study populations, variable dosing, and potential selection bias in EID study populations. In contrast to clinical outcomes, model-based simulations of natalizumab exposure suggest that EID regimens (6-8 week intervals) may not provide adequate protection from MS disease activity. 19 Given the uncertainties regarding the long-term benefit profile of natalizumab EID, it is premature to suggest that SID should be replaced with EID. Planned, randomized, prospective studies comparing EID versus SID will provide a more comprehensive understanding of both the efficacy and safety of natalizumab EID.

[0299] References 1. Miller DH, Khan OA, Sheremata WA, et al.A controlled trial of natalizumab for relapsing multiple sclerosis.N Engl J Med 2003;348:15-23. 2.Polman CH, O'Connor PW, Havrdova E, et al.A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis.N Engl J Med 2006;354:899-910. 3. Prosperini L, Sacca F, Cordioli C, et al. Real-world effectiveness of natalizumab and fingolimod compared with self-injectable drugs in non-responders and in treatment-naive patients with multiple sclerosis. J Neurol 2017;264:284-294. 4. Butzkueven H, Kappos L, Pellegrini F, et al. Efficacy and safety of natalizumab in multiple sclerosis: interim observational programme results. J Neurol Neurosurg Psychiatry 2014;85:1190-1197. 5. Rudick RA, Sandrock A. Natalizumab: a4-integrin antagonist selective adhesion molecule inhibitors for MS. Expert Rev Neurother 2004;4:571-580. 6. Stuve O, Bennett JL. Pharmacological properties, toxicology and scientific rationale for the use of natalizumab (Tysabri) in inflammatory diseases. CNS Drug Rev 2007;13:79-95. 7. Tysabri (registered trademark) (natalizumab) [prescription information]. Cambridge, MA: Biogen, 2018. 8. Bloomgren G, Richman S, Hotermans C, et al. Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med 2012;366:1870-1880. 9. Ho P-R, Koendgen H, Campbell N, Haddock B, Richman S, Chang I. Risk of natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: a retrospective analysis of data from four clinical studies. Lancet Neurol 2017;16:925-933. 10. Bomprezzi R, Pawate S. Extended inter val dosing of natalizumab: a two-center, 7-year experience. Ther Adv Neurol Disord 2014;7:227-231. 11. Zhovtis Ryerson L, Frohman TC, Foley J, et al. Extended interval dosing of natalizumab in multiple sclerosis. J Neurol Neurosurg Psychiatry 2016;87:885-889. 12. Risk Evaluation and Mitigation Stra tegy(REMS): TYSABRI Outreach: Unified Commitment to Health(TOUCH(registered trademark)) Prescribing Program [Documentation].Download:www.fda.gov / downloads / Drugs / DrugSafety / PostmarketDrugS afetyInformationforPatientsandProviders / UCM288126.pdf.(accessed May 19, 2018) 13. Hervas-Garcia JV,Presas-Rodriguez S ,Crespo-Cuevas AM,et al.Progressive multifocal leukoencephalopathy associated with natalizumab extended dosing regimen.Neurodegenr Dis Manag 2015;5:399-402. [ PubMed ] 14. Plavina T, Muralidharan KK, Kuesters G,et al.Reversibility of the effects of natalizumab on peripheral immune cell dynamics in MS patients.Neurology 2017;89:1584-1593. [ PubMed ] 15. Fox RJ,Cree BA,De Seze J,et al.MS d isase activity in RESTORE:a randomized 24-week natalizumab treatment interruption study.Neurology 2014;82:1491–1498. [ PubMed ] 16. Kappos L,Radue EW,Comi G,et al.Swit ching from natalizumab to fingolimod:A randomized,placebo-controlled study in RRMS.Neurology 2015;85:29-39. [ PubMed ] 17. Grimaldi LM,Prosperini L,Vitello G, Borriello G, Fubelli F, Pozzilli C. MRI-based analysis of the natalizumab therapeutic window in multiple sclerosis.Mult Scler 2012;18:1337-1339. 18. Berkovich R, Togasaki DM, Cen SY, Stei nman L.CD4 cell response to interval therapy with natalizumab.Ann Clin Transl Neurol 2015;2:570-574. 19. Muralidharan KK, Steiner D, Amarante D,et al.Exposure-disease response analysis of natalizumab in subjects with multiple sclerosis.J Pharmacokinet Pharmacodyn 2017;44:263-275.

[0300] Example 8: The efficacy and safety of natalizumab administration at 6-week intervals will be evaluated in a prospective, controlled, randomized, open-label, evaluator-blinded Phase 3b trial (NOVA). preface Natalizumab, a highly effective treatment for relapsing-remitting multiple sclerosis (RRMS), is also associated with a risk of PML. (1-5) Recent analyses of the TOUCH dataset have demonstrated that EID is associated with a significantly lower risk of PML than standard interval dosing (SID) in patients positive for anti-JC virus antibodies. (6) To date, there are no randomized studies comparing the efficacy of natalizumab EID and SID. Without promising randomized efficacy data, the benefit-benefit profile of EID is not established.

[0301] the purpose This paper describes the design of a phase 3b study to evaluate the effectiveness of switching to EID natalizumab after a stable period of SID compared to the duration of SID.

[0302] method The natalizumab, Phase 3b, Prospective, Randomized, Open-Labeled Trial (NOVA) comparing extended interval dosing versus approved dose will be an interventional, controlled, assessor-blinded, overall trial (clinicaltrials.gov no.NCT03689972). Patient selection criteria include being 18–60 years of age, Expanded Disability Status Scale score ≤5.5, diagnosis of RRMS, stability with natalizumab SID (11 or more doses received, no relapses in the past 12 months), no history of immunosuppressant use, and no gadolinium-enhancing (Gd+) lesions at screening.

[0303] Approximately 480 patients will be enrolled in NOVA. Patients will be randomized in a 1:1 ratio to receive either natalizumab SID (300 mg intravenously [IV] every 4 weeks [26-33 days]) or EID (300 mg intravenously [IV] every 6 weeks [40-47 days]). The study period will be 88 weeks (4 weeks of screening, 72 weeks of randomization treatment, and 12 weeks of follow-up) (Figure 18).

[0304] The primary endpoint is the number of new / newly expanding T2 lesions at 48 weeks. Key secondary endpoints include time to recurrence, recurrence rate, number of new radiation lesions, and incidence of serious adverse events. Exploratory endpoints include a timed 25-foot walk (T25FW), a 9-hole peg test (9HPT), and Symbol Digit Modality Test (SDMT) scores, as well as confirmation of disability progression or improvement.

[0305] We will collect data on natalizumab serum concentration, alpha-4 integrin saturation, lymphocyte count, and body weight to investigate the relationship between pharmacokinetics (PK) / pharmacodynamics (PD) and efficacy.

[0306] Research arguments The EID interval for NOVA was selected to include the actual medication interval associated with a lower risk of PML observed in the TOUCH analysis (Figure 19). (6) The rationale for requiring disease stability of SID for 12 months or more in SID before random assignment to switch to EID is as follows: an independent study suggested comparable efficacy between SID and EID in patients switched to EID 1-2 years after SID. (7-9) Modeling has shown that initiating patients with EID may result in insufficient protection from clinical and magnetic resonance imaging (MRI) disease activity. (10) Analysis of AFFIRM patients demonstrated improved efficacy of natalizumab after the first year of treatment (Figure 20A). (11)

[0307] Analysis of a pooled cohort of patients from four open-label clinical trials of natalizumab has shown that the risk of PML is low in the first year of treatment, regardless of immunosuppressant index or prior use (Figure 20B). (12) Therefore, we hypothesize that the incentive for EID as a PML risk reduction strategy is low in the first year of treatment.

[0308] The number of new or newly expanding T2 high-intensity lesions at 48 weeks for the selection of the primary endpoint is an objective and highly sensitive indicator of the efficacy of natalizumab. In open-label trials, rater-blinded MRI endpoints remain fully objective, while recurrence-based endpoints tend to be biased in these situations. T2 high-intensity lesions represent a persistent footprint of demyelination and provide highly sensitive detection of disease activity. (13) The sample size (N=480) provides over 80% power and detects a difference between 0.3 (the predicted value for the SID group in this population) and 0.5 in the mean number of new or newly expanding T2 lesions.

[0309] literature Endoadjusted intravenous administration (EID) is practiced by some physicians as an off-label strategy to mitigate the risk of natalizumab-associated PML. Several retrospective studies have suggested that the efficacy of natalizumab may be maintained even if the EID dosing schedule extends beyond 4 weeks. (7, 8) However, a partial reversal of the pharmacodynamic effect of natalizumab has been reported to occur 4–8 weeks after the last dose. (17) This study provides the first randomized, controlled efficacy data from patients treated with natalizumab EID, leading to a more comprehensive understanding of both the efficacy and safety of natalizumab EID.

[0310] References 1.Miller DH,et al.N Engl J Med.2003;348:15-23; 2.Polman CH,et al.N Engl J Med.2006;354:899-910; 3.Prosperini L,et al.J Neurol.2017;264:284-294; 4.Butzkueven H,et al.J Neurol Neurosurg Psychiatry.2014;85:1190-1197; 5. Tysabri® (Natalizumab) [Prescription Information]. Cambridge, MA: Biogen, 2018; 6.Zhovtis Ryerson L,et al.Presented at ACTRIMS;February 1-3,2018;San Diego,CA.LB250; 7.Zhovtis Ryerson L,et al.J Neurol Neurosurg Psychiatry.2016;87:885-889; 8. Bomprezzi R, Pawate S, Ther Adv Neurol Disord.2014;7:227-231; 9.Muralidharan KK,et al.Presented at ECTRIMS;September 14-17,2016;London,UK.P1672; 10.Muralidharan KK,et al.J Pharmacokinet Pharmacodyn.2017;44:263- 275; 11.Havrdova E,et al.Lancet Neurol.2009;8:254-260; 12.Ho PR,et al.Lancet Neurol.2017;16:925-933; 13. Rovira A,et al.Ther Adv Neurol Disord.2013;6:298-310; 15.Campagnolo D,et al.Neurology.2016;87(2):e25; 16.O'Connor P,et al.Neurology.2014;83:78-86; 16.Foley J,et al.Mult Scler.2016;22(Suppl 3):646-647.P1229; 17.Plavina T et al.Neurology.2017;89:1584-1593. ***

[0311] All references, patents, and patent applications disclosed herein are incorporated by reference, in whole and for any purpose, and in particular with respect to the subject matter from which each is cited, which may in some cases encompass the entire document.

[0312] In this specification and in the claims, the indefinite articles "a" and "an" as used herein should be understood to mean "at least one" unless explicitly stated otherwise.

[0313] Conversely, unless explicitly stated otherwise, in any method claimed herein that includes two or more steps or actions, the order of the steps or actions of the method is not necessarily limited to the order in which the steps or actions of the present invention are enumerated.

[0314] In the claims and the above specification, all transitional phrases such as “comprising,” “including,” “carrying,” “having,” “containing,” “involving,” “holding,” and “composed of” should be understood to mean including without restriction, that is, without limitation. Only the transitional phrases “consisting of” and “consisting essentially of” are considered closed or semi-closed transitional phrases, respectively, as provided in Section 2111.03 of the U.S. Patent and Trademark Office Manual of Patent Examination Procedure.

[0315] The terms "approximately" and "effectively" preceding numerical values ​​mean ±10% of the listed values.

[0316] Where a range of values ​​is provided, each value between the upper and lower limits of the range is specifically intended and described herein.

[0317] Embodiment Exemplary embodiments include a method for reducing the risk of developing progressive multifocal leukemia (PML) in subjects, the method including: a. identifying subjects at low PML risk receiving natalizumab therapy on a standard interval dosing (SID) schedule of 4 weeks apart; b. determining whether a subject has been switched from a low PML risk to a high PML risk during natalizumab therapy; and c. if a subject has been switched to a high PML risk, identifying high PML risk subjects for natalizumab therapy on an extended interval dosing (EID) schedule of intervals greater than 4 weeks (e.g., at least 5 weeks apart).

[0318] Exemplary embodiments include a method that involves administering natalizumab to subjects having an anti-JCV antibody index level of 0.9 or less in a 4-week interval SID schedule, and then, after the subjects have an anti-JCV antibody index level of 1.5 or higher, administering natalizumab therapy to the subjects in an extended interval dosing (EID) schedule at intervals greater than 4 weeks (e.g., at least 5 weeks).

[0319] Exemplary embodiments include a method for reducing the risk of developing PML in a subject, which includes: a) administering a therapeutically effective dose of natalizumab to the subject in a 4-week interval SID schedule, provided that the subject is at low PML risk; b) determining whether the subject has transitioned from low PML risk to high PML risk during SID natalizumab therapy; and c) if the subject has transitioned to high PML risk, administering a therapeutically effective dose of natalizumab to the subject in an EID schedule at least 5-week intervals.

[0320] An exemplary embodiment includes a method for reducing the risk of developing PML in subjects, the method comprising identifying subjects for natalizumab therapy on an EID schedule at least 5-week intervals, where the subjects are tested for seropositive for anti-JCV antibodies and are receiving natalizumab therapy on an SID schedule at 4-week intervals.

[0321] An exemplary embodiment includes a method for reducing the risk of developing PML in a subject, the method comprising administering a therapeutically effective dose of natalizumab to the subject in an EID schedule at least 5-week intervals, wherein the subject has been tested for seropositive for anti-JCV antibody and is receiving natalizumab therapy in a SID schedule at 4-week intervals.

[0322] Exemplary embodiments include a method for reducing the risk of developing PML in subjects, which includes a. identifying subjects who have been tested for serological positivity for anti-JCV antibodies and have received natalizumab therapy in a 4-week interval SID schedule; and b. administering a therapeutically effective dose of natalizumab to the subjects in an EID schedule at least 5-week intervals.

[0323] Exemplary embodiments include a method for treating multiple sclerosis (MS) in subjects, the method comprising: a. identifying low-PML risk subjects with MS receiving natalizumab therapy on a standard interval dosing (SID) schedule of 4 weeks apart; b. determining whether a subject has been switched from a low-PML risk subject to a high-PML risk subject during natalizumab therapy; and c. if a subject has been switched to a high-PML risk subject, identifying high-PML risk subjects for natalizumab therapy on an extended interval dosing (EID) schedule of at least 5 weeks apart.

[0324] Exemplary embodiments include a method for treating Crohn's disease in subjects, the method comprising: a. identifying subjects with Crohn's disease at low PML risk who are receiving natalizumab therapy on a standard interval dosing (SID) schedule of 4 weeks apart; b. determining whether a subject has been switched from a low PML risk subject to a high PML risk subject during natalizumab therapy; and c. if a subject has been switched to a high PML risk subject, identifying high PML risk subjects for natalizumab therapy on an extended interval dosing (EID) schedule of at least 5 weeks apart.

[0325] Exemplary embodiments include a method for treating epilepsy in subjects, the method comprising: a. identifying subjects with epilepsy at low PML risk who are receiving natalizumab therapy on a standard interval dosing (SID) schedule of 4 weeks apart; b. determining whether a subject has been switched from a low PML risk subject to a high PML risk subject during natalizumab therapy; and c. if a subject has been switched to a high PML risk subject, identifying high PML risk subjects for natalizumab therapy on an extended interval dosing (EID) schedule of at least 5 weeks apart.

[0326] In some of the one or more exemplary embodiments, step (a) includes identifying low-PML risk subjects having an anti-JCV antibody index level of 0.9 or less. In some of the one or more exemplary embodiments, step (b) includes determining the anti-JCV antibody index level of the subjects. In some of the one or more exemplary embodiments, high-PML risk subjects in step (c) have an anti-JCV antibody index level greater than 1.5. In some of the one or more exemplary embodiments, high-PML risk subjects in step (c) have an anti-JCV antibody index level greater than 0.9.

[0327] In some of the one or more exemplary embodiments, subjects receiving natalizumab therapy on an extended interval dosing (EID) schedule have an anti-JCV antibody index level greater than 1.5. In some of the one or more exemplary embodiments, subjects receiving natalizumab therapy on an extended interval dosing (EID) schedule have an anti-JCV antibody index level greater than 0.9. In some of the one or more exemplary embodiments, subjects receiving natalizumab therapy on a standard interval dosing (SID) schedule have an anti-JCV antibody index level of 0.9 or less.

[0328] In some of the one or more exemplary embodiments, for example, a sample(s) derived from a subject previously obtained from a subject receiving natalizumab therapy on an extended interval dosing (EID) schedule after natalizumab therapy on a standard interval dosing (SID) schedule has an anti-JCV antibody index level greater than 1.5. In some of the one or more exemplary embodiments, for example, a sample(s) derived from a subject previously obtained from a subject receiving natalizumab therapy on an extended interval dosing (EID) schedule after natalizumab therapy on a standard interval dosing (SID) schedule has an anti-JCV antibody index level greater than 0.9. In some of the one or more exemplary embodiments, for example, a sample(s) derived from a control previously obtained from a subject receiving natalizumab therapy on an extended interval dosing (EID) schedule prior to the extended interval dosing (EID) has an anti-JCV antibody index level of 0.9 or less.

[0329] In some of the exemplary embodiments, natalizumab therapy on an EID schedule is administered at intervals of 5 to 10 weeks. In some of the exemplary embodiments, natalizumab therapy on an EID schedule is administered at intervals of 5 to 8 weeks. In some of the exemplary embodiments, natalizumab therapy on an EID schedule is administered at intervals of more than 4 weeks but no more than 12 weeks. In some of the exemplary embodiments, natalizumab therapy on an EID schedule is administered at intervals of more than 4 weeks but no more than 10 weeks. In some of the exemplary embodiments, natalizumab therapy on an EID schedule is administered at intervals of more than 4 weeks but no more than 8 weeks. In some of the exemplary embodiments, natalizumab therapy on an EID schedule is administered at intervals of more than 4 weeks but no more than 6 weeks. In some of the exemplary embodiments, natalizumab therapy on an EID schedule is administered at intervals of 6 weeks. In some cases of one or more exemplary embodiments, natalizumab therapy in an EID schedule is administered at 7-week intervals. In some cases of one or more exemplary embodiments, natalizumab therapy in an EID schedule is administered at 8-week intervals. In some cases of one or more exemplary embodiments, natalizumab therapy in an EID schedule is administered at 9-week intervals.

[0330] In some of the one or more exemplary embodiments, the subject receives natalizumab therapy on a SID schedule at 4-week intervals for at least 6 months, 1 year, 18 months, 2 years, or 5 years. In some of the one or more exemplary embodiments, the subject receives natalizumab therapy on a SID schedule at 4-week intervals for at least 6 months, 1 year, 18 months, 2 years, or 5 years. In some of the one or more exemplary embodiments, the subject is administered natalizumab therapy on a SID schedule at 4-week intervals for at least 6 months, 1 year, 18 months, 2 years, or 5 years.

[0331] In some of the one or more exemplary embodiments, the subject is diagnosed with an autoimmune condition. In some of the one or more exemplary embodiments, the subject has an autoimmune condition. In some of the one or more exemplary embodiments, the subject's autoimmune condition is treated with natalizumab therapy. In some of the one or more exemplary embodiments, the autoimmune condition is multiple sclerosis. In some of the one or more exemplary embodiments, the autoimmune condition is Crohn's disease. In some of the one or more exemplary embodiments, the autoimmune condition is rheumatoid arthritis.

[0332] In some of the one or more exemplary embodiments, the subject is diagnosed with epilepsy. In some of the one or more exemplary embodiments, the subject has epilepsy. In some of the one or more exemplary embodiments, the subject's autoimmune condition is treated with natalizumab therapy.

[0333] In some of the one or more exemplary embodiments, the subjects have a history of immunosuppression. In some of the one or more exemplary embodiments, the subjects were treated with an immunosuppressant before receiving natalizumab therapy on a 4-week interval SID schedule. In some of the one or more exemplary embodiments, the single dose of natalizumab is 300 mg. In some of the one or more exemplary embodiments, the risk of developing PML in the subjects is reduced by at least 10% compared to the risk of developing PML in subjects receiving natalizumab therapy on a 4-week interval SID schedule. In some of the one or more exemplary embodiments, the risk of developing PML in the subjects is reduced by at least 20% compared to the risk of developing PML in subjects receiving natalizumab therapy on a 4-week interval SID schedule. In some of the one or more exemplary embodiments, the risk of developing PML in the subjects is reduced by at least 50% compared to the risk of developing PML in subjects receiving natalizumab therapy on a 4-week interval SID schedule.

[0334] In some cases of one or more exemplary embodiments, the efficacy of natalizumab therapy on the EID schedule is 80% or at least 80% of the efficacy of natalizumab therapy on the SID schedule. In some cases of one or more exemplary embodiments, the efficacy of natalizumab therapy on the EID schedule is 90% or at least 90% of the efficacy of natalizumab therapy on the SID schedule.

[0335] In some cases of one or more exemplary embodiments, the efficacy of natalizumab therapy includes maintaining trough α4-integrin saturation (>50%). In some cases of one or more exemplary embodiments, natalizumab therapy on an EID schedule maintains trough α4-integrin saturation of at least, or at least about 65%. In some cases of one or more exemplary embodiments, the efficacy of natalizumab therapy includes the mean risk of Gd+ lesions at week 48 of natalizumab therapy on an EID and / or SID schedule. In some cases of one or more exemplary embodiments, natalizumab therapy on an EID schedule demonstrates a mean risk of Gd+ lesions at week 48 of natalizumab therapy on an EID schedule of about 20%, 15%, 10%, or less than 5%. In some cases of one or more exemplary embodiments, natalizumab therapy on an EID schedule exhibits a mean risk of Gd+ lesions at week 48 of natalizumab therapy on an EID schedule of approximately 0.1% to approximately 20%, approximately 0.1% to approximately 15%, approximately 0.1% to approximately 10%, or approximately 0.1% to approximately 5%.

[0336] In some cases of one or more exemplary embodiments, the efficacy of natalizumab therapy includes the mean expected number of Gd+ lesions at week 48 of natalizumab therapy on an EID and / or SID schedule. In some cases of one or more exemplary embodiments, natalizumab therapy on an EID schedule shows a mean expected number of Gd+ lesions at week 48 of natalizumab therapy on an EID schedule of approximately 1.5, 1.25, 1, 0.8, 0.65, 0.4, 0.2, or less than 0.15. In some cases of one or more exemplary embodiments, EID-scheduled natalizumab therapy shows a mean expected number of Gd+ lesions at week 48 of EID-scheduled natalizumab therapy in the ranges of approximately 0 to approximately 1.5, approximately 0 to approximately 1.25, approximately 0 to approximately 1, approximately 0 to approximately 0.8, approximately 0 to approximately 0.65, approximately 0 to approximately 0.4, approximately 0 to approximately 0.2, or approximately 0 to approximately 0.15.

[0337] In some cases of one or more exemplary embodiments, the efficacy of natalizumab therapy includes the cumulative probability of relapse at week 48 with natalizumab therapy in the EID and / or SID schedule. In some cases of one or more exemplary embodiments, natalizumab therapy in the EID schedule shows a cumulative probability of relapse at week 48 with natalizumab therapy in the EID schedule of about 30%, 27%, 25%, 20%, 15%, or less than 10%. In some cases of one or more exemplary embodiments, natalizumab therapy in the EID schedule shows a cumulative probability of relapse at week 48 with natalizumab therapy in the EID schedule of about 5% to about 30%, about 5% to about 25%, about 5% to about 20%, or about 5% to about 15%.

[0338] In some cases of one or more exemplary embodiments, the subject weighs less than approximately 120 kg. In some cases of one or more exemplary embodiments, the subject weighs less than approximately 100 kg. In some cases of one or more exemplary embodiments, the subject weighs less than approximately 99 kg. In some cases of one or more exemplary embodiments, the subject weighs less than approximately 80 kg. In some cases of one or more exemplary embodiments, the subject weighs at least approximately 40 kg. In some cases of one or more exemplary embodiments, the subject weighs between approximately 40 kg and less than approximately 120 kg. In some cases of one or more exemplary embodiments, the subject weighs between approximately 40 kg and less than approximately 100 kg. In some cases of one or more exemplary embodiments, the subject weighs between approximately 40 kg and less than approximately 80 kg. The present invention provides, for example, the following items. (Item 1) A method for improving the safety of chronic natalizumab therapy in a patient in need thereof, comprising determining whether the patient has at least one risk factor for progressive multifocal encephalopathy (PML), and administering natalizumab to the patient in an EID schedule including intervals of at least 5 weeks, in the presence of the at least one risk factor. (Item 2) The method according to item 1, wherein the at least one risk factor includes prior immunosuppression in the patient. (Item 3) The method according to any one of the preceding items, wherein the at least one risk factor includes or further includes the presence of serum anti-JCV antibodies in the patient. (Item 4) The method according to any one of the preceding items, wherein the at least one risk factor includes the presence of anti-JCV antibodies in the patient, and the determination step includes determining the anti-JCV antibody status of the patient, and if the patient is serologically positive for JCV antibodies, administering natalizumab to the patient in an EID schedule at intervals of at least 5 weeks. (Item 5) The method according to any one of the preceding items, wherein the patient has an anti-JCV antibody index greater than 0.9. (Item 6) The method according to item 5, wherein the patient has an anti-JCV antibody index level greater than 1.5. (Item 7) The method according to any one of the preceding items, wherein if at least one of the risk factors includes the length of previous natalizumab treatment and the patient has received natalizumab therapy for more than six months, the method comprises administering natalizumab to the patient in an EID schedule at intervals of at least five weeks. (Item 8) The method according to any one of the preceding items, wherein at least one of the risk factors includes the length of prior natalizumab treatment, the patient has received natalizumab therapy for more than six months, and the method comprises administering natalizumab to the patient in an EID schedule with at least five-week intervals. (Item 9) The method described in item 7 or 8, wherein the natalizumab therapy exceeding six months is natalizumab therapy exceeding six months on the SID schedule. (Item 10) The method described in any one of the preceding items, wherein the interval of the EID schedule is 5 to 8 weeks. (Item 11) The method described in any one of the preceding items, wherein the interval of the EID schedule is 5 to 7 weeks. (Item 12) The method described in any one of the preceding items, wherein the interval of the EID schedule is 6 weeks. (Item 13) The method according to any one of the preceding items, wherein the EID schedule maintains an average trough α4-integrin receptor saturation of more than 50% in the EID patient population. (Item 14) The method according to item 13, wherein the EID schedule maintains an average trough α4β1-integrin receptor saturation of more than 65% in the EID patient population. (Item 15) A method described in any one of the preceding items, a. The patient's weight is less than approximately 120 kg; or b. The patient's weight is less than approximately 100 kg; or c. The patient's weight is less than approximately 80 kg; or d. The patient's weight is between approximately 40 kg and less than approximately 120 kg; or e. The patient's weight is between approximately 40 kg and less than approximately 80 kg; or f. The method wherein the patient's weight is between approximately 40 kg and less than approximately 60 kg. (Item 16) The method according to item 15, wherein the patient's weight is approximately 40 kg to approximately 80 kg, and the EID schedule has intervals of at least 5 weeks and no more than 7 weeks. (Item 17) The method according to item 16, wherein the patient's weight is approximately 40 kg to approximately 80 kg, and the EID schedule has intervals of 6 weeks. (Item 18) The patient's weight is approximately 40 kg to 60 kg, and the EID schedule is 6 weeks to The method according to item 16, wherein the interval is 7 weeks, preferably 6 weeks. (Item 19) The method according to any one of the preceding items, wherein the EID schedule includes a dose of 300 milligrams. (Item 20) The method according to any one of items 1 to 18, wherein the EID schedule includes a dose equivalent to 3.75 to 7.5 mg of natalizumab per kg of patient body weight. (Item 21) The method described in any one of the preceding items, wherein the patient has an autoimmune disease. (Item 22) The method according to item 21, wherein the aforementioned autoimmune disease is MS. (Item 23) The method according to item 21, wherein the autoimmune disease is inflammatory bowel disease. (Item 24) The method according to item 21, wherein the autoimmune disease is Crohn's disease. (Item 25) The method described in any one of items 1 to 20, wherein the patient suffers from epilepsy. (Item 26) A method for administering natalizumab therapy to a patient in need thereof, comprising administering the natalizumab therapy on an EID schedule, wherein a. The patient's weight range is between 40 kg and less than 80 kg; and b. The method wherein the PML risk of natalizumab therapy is reduced compared to natalizumab therapy on the SID schedule. (Item 27) The method according to item 26, wherein the EID schedule includes a dose of 300 milligrams. (Item 28) The method according to item 26 or 27, wherein the EID schedule includes a dose equivalent to 3.75 to 7.5 mg of natalizumab per kg of patient body weight. (Item 29) The method according to item 26, 27, or 28, wherein the efficacy of natalizumab therapy in the EID schedule is 20% or less lower compared to natalizumab therapy in the SID schedule. (Item 30) The method described in any one of items 26-29, wherein the risk of Gd+ lesions at week 48 of natalizumab therapy in the EID schedule increases by approximately 10% or less, the mean number of expected Gd+ lesions at week 48 of natalizumab therapy in the EID schedule increases by approximately 0.65 or less, and / or the cumulative probability of clinical relapse at week 48 of natalizumab therapy in the EID schedule increases by approximately 15% or less. (Item 31) The method according to any one of items 26-30, wherein the EID schedule maintains an average trough α4-integrin receptor saturation of more than 60%. (Item 32) The method according to item 31, wherein the EID schedule maintains an average trough α4β1-integrin receptor saturation of more than 65%. (Item 33) The method according to any one of items 26 to 32, wherein the patient's weight is approximately 40 kg to approximately 80 kg, and the EID schedule has intervals of at least 5 weeks and no more than 7 weeks. (Item 34) The method according to item 33, wherein the patient's weight is approximately 40 kg to approximately 80 kg, and the EID schedule has a 6-week interval. (Item 35) The method according to item 33, wherein the patient's weight is approximately 40 kg to approximately 60 kg, and the EID schedule has intervals of 6 to 7 weeks, preferably 6 weeks. (Item 36) The method according to any one of items 26 to 35, comprising administering the natalizumab in the EID schedule for at least 6 months, at least 1 year, at least 18 months, at least 2 years, or at least 5 years. (Item 37) A method for improving the safety of chronic natalizumab therapy in a patient in need thereof, comprising: determining whether the patient has at least one risk factor for progressive multifocal encephalopathy (PML); and, in the presence of the at least one risk factor, administering natalizumab to the patient at a dose of 300 milligrams in an EID schedule with intervals of at least 5 weeks and no more than 7 weeks, wherein the patient's weight is approximately 40 kg to approximately 80 kg. (Item 38) A method for administering natalizumab therapy to a patient in need thereof, the method comprising administering the natalizumab therapy in doses of 300 milligrams in an EID schedule having intervals of at least 5 weeks and no more than 7 weeks, wherein a. The patient's weight range is between 40 kg and less than 80 kg; and b. The method wherein the PML risk of natalizumab therapy is reduced compared to natalizumab therapy on the SID schedule. (Item 39) A method for improving the safety of chronic natalizumab therapy in a patient in need thereof, comprising: determining whether the patient has at least one risk factor for progressive multifocal encephalopathy (PML); and, in the presence of the at least one risk factor, administering natalizumab to the patient at a dose equivalent to 3.75 to 7.5 mg of natalizumab per kg of body weight in an EID schedule with intervals of at least 5 weeks and no more than 7 weeks. (Item 40) A method for administering natalizumab therapy to a patient in need thereof, the method comprising administering the natalizumab therapy to the patient in a dose equivalent to 3.75 to 7.5 mg of natalizumab per kg of the patient's body weight in an EID schedule having intervals of at least 5 weeks and no more than 7 weeks, wherein the PML risk of the natalizumab therapy is reduced compared to natalizumab therapy in an SID schedule. (Item 41) A method for administering natalizumab therapy to a patient in need thereof, the method comprising administering the natalizumab therapy for 12 months in an SID schedule, and then administering the natalizumab therapy in an EID schedule. (Item 42) The method according to item 41, wherein the dose of natalizumab therapy in the SID schedule is 300 mg. (Item 43) The method according to item 41 or 42, wherein the dose of natalizumab therapy in the EID schedule is 300 mg. (Item 44) The method according to item 41, wherein the method comprises administering the natalizumab therapy in the EID schedule at a dose equivalent to 3.75 to 7.5 mg of natalizumab per kg of the patient's body weight. (Item 45) The above method corresponds to 3.75 to 7.5 mg of natalizumab per kg of the patient's body weight. The method according to item 41 or 44, comprising administering the natalizumab therapy in the SID schedule at the dose. (Item 46) The method according to any one of items 41 to 45, wherein the EID schedule has intervals of at least 5 weeks and 7 weeks or less, preferably at least 5 weeks and 7 weeks or less. (Item 47) The method described above for item 46, wherein the EID schedule has a 6-week interval. (Item 48) The method according to any one of items 41 to 45, wherein the patient's weight is less than 120 kg, preferably between approximately 40 kg and less than 120 kg. (Item 49) The method according to item 48, wherein the patient's weight is less than 100 kg, preferably between approximately 40 kg and less than 100 kg. (Item 50) The method according to item 48, wherein the patient's weight is less than 80 kg, preferably between approximately 40 kg and less than 80 kg. (Item 51) The method according to item 48, wherein the patient's weight is less than 60 kg, preferably between approximately 40 kg and less than 60 kg.

Claims

[Claim 1] The invention as shown in the drawings.

Images