Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Natalizumab · 22 trials · 11 indications
T2 hyperintense lesions were analyzed by magnetic resonance imaging (MRI) scans of brain. New MRI scans were compared with the prior MRI scans to analyze the number of new or newly enlarging T2 hyperintense lesions at Week 72 relative to baseline.
The primary endpoint for this clinical study is the proportion of complete response, CR (that is, the percent of patients with skin, liver, and GI GVHD - all stage 0) at day 28 of study treatment. Stage 0 = no rash, total bilirubin \<2 mg/dl, diarrhea \<500 ml/d
Graft-versus-host disease (GVHD) free survival is defined as achieving complete response without death or relapse or requiring secondary immunosuppressive therapy . Proportions are reported descriptively. GVHD-free survival was assessed using the Kaplan-Meier method.
The primary endpoint is change in CSF osteopontin from baseline to week 60.
Seizures included were focal aware seizures with motor signs, focal impaired awareness seizures and focal to bilateral tonic-clonic seizure. Focal aware seizures without motor signs were not included. Seizure clusters (where individual seizures cannot be distinguished) were counted as 1 seizure per cluster on each day that they are present. Study baseline seizure frequency (number of seizures per 28 days) was calculated based on participant's seizure diary data during prospective baseline phase. Seizure frequency (SF) at post baseline visit was calculated based on sum of the seizures reported in participant seizure diary and the number of days with non-missing SF data in participant seizure diary on or after the previous visit date. Change from Baseline are based on natural log transformation of baseline SF or SF at post baseline visit correspondingly. For log-transformation, the quantity 0.2 {ln(x+0.2)} was added to the SF at post baseline visit to account for 0 seizure count.
The composite global measure of functional disability excellent outcome was based on a score of 0 or 1 on the modified Rankin Scale (mRS) and a score of \>=95 on the Barthel Index (BI). mRS measures independence, rather than neurological function, with specific tasks pre- and post-stroke. The scale consists of 7 grades, from 0 to 6, with 0 corresponding to no symptoms and 6 corresponding to death. BI consists of 10 items that measure a participant's daily functioning, specifically the activities of daily living and mobility. The items include feeding, moving from wheelchair to bed and returning, grooming, transferring to and from a toilet, bathing, walking on a level surface, going up and down stairs, dressing, and maintaining continence of bowels and bladder. The scores for each of the items are summed to create a total score of 0 to 100. The higher the score, the more "independent" the participant is.
Relative growth of infarct volume from Baseline (relative growth = FLAIR at Day 5 divided by Baseline DWI). Geometric mean calculated as the exponential of the mean log relative growth.
Cumulative number of combined unique active lesions (sum of the number of new gadolinium (Gd)-enhancing lesions and new or newly enlarging T2 hyperintense lesions not associated with Gd-enhancement on T1 weighted scans) based on brain magnetic resonance imaging (MRI) scans Up to Week 60.
AE=any untoward medical occurrence that did not necessarily have a causal relationship with this treatment. Serious AE (SAE)=any untoward medical occurrence that at any dose: resulted in death; in the view of the Investigator, was a life threatening event; required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; resulted in a congenital anomaly/birth defect; or any other medically important event that, in the opinion of the Investigator, may have jeopardized the participant or may have required intervention to prevent one of the other outcomes listed in the definition above. Events were categorized as related or not related; severity was categorized as mild, moderate, or severe.
New active lesions were the sum of the gadolinium-enhancing (Gd+) lesions and any new or newly enlarging T2 hyperintense lesions that did not enhance as seen on cranial magnetic resonance imaging (MRI) scans. The rate is calculated for each participant as the ordinary least squares slope of the cumulative new active lesions over time.
An AE was any untoward medical occurrence that did not necessarily have a causal relationship with this treatment. An SAE was any untoward medical occurrence that at any dose: resulted in death; in the view of the Investigators, placed the subject at immediate risk of death (a life-threatening event); however, this did not include an event that, had it occurred in a more severe form, might have caused death; required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; resulted in a congenital anomaly/birth defect; any other medically important event that, in the opinion of the Investigators, could have jeopardized the subject or may have required intervention to prevent one of the other outcomes listed in the definition above.
Negative is defined as negative for antibodies at all post-baseline results. Transient positivity is defined as only 1 positive result. Persistent positivity is defined as 2 positive results separated by at least 6 to 12 weeks.
Rescue criteria were: 1) central reader MRI finding of 1 new gadolinium-enhancing (Gd+) lesion of \>0.8 cubic centimeters in volume or 2 or more Gd+ lesions of any size 2) clinical relapse. Clinical relapse was new or recurrent neurological symptoms not associated with fever or infection, lasting at least 24 hours, as defined by: an increase of ≥1 grade in ≥2 functional scales of the Expanded Disability Status Scale (EDSS); an increase of ≥2 grades in 1 functional scale of the EDSS; or an increase of \>0.5 in EDSS if the previous EDSS was ≤5.5, or ≥0.5 if the previous EDSS was \>5.5
Area under the curve to the last measurable concentration as measured by the trapezoidal rule.
PD activity will be assessed by measuring the degree of natalizumab saturation of the very late antigen-4 (also known as α4β1 integrin) VLA-4 (α4β1) receptor on peripheral blood lymphocyte/monocyte populations.
| Arm | Type | Description |
|---|---|---|
| Part 1: IV Q4W | EXPERIMENTAL | Participants received natalizumab 300 mg intravenous (IV) infusion once Q4W up to Week 72. |
| Part 1: IV Q6W | EXPERIMENTAL | Participants received natalizumab 300 mg IV infusion once Q6W up to Week 72. |
| Part 2: Run-in Period: IV Q6W | EXPERIMENTAL | Participants who completed Part 1 or were newly enrolled in Part 2 received natalizumab 300 mg IV infusion Q6W from Week 72 through Week 102. |
| Part 2: Crossover Period: IV Q6W, then SC Q6W | EXPERIMENTAL | Participants who completed run-in period of Part 2 were randomized to receive natalizumab 300 mg IV infusion Q6W from Week 108 through Week 126 followed by natalizumab 300 mg subcutaneous (SC) injection Q6W from Week 132 through Week 150 along with a single dose of natalizumab 300 mg SC injection or IV infusion as per participant's choice at Week 156. |
| Part 2: Crossover Period: SC Q6W, then IV Q6W | EXPERIMENTAL | Participants who completed run-in period of Part 2 were randomized to receive natalizumab 300 mg SC injection Q6W from Week 108 through Week 126 followed by natalizumab 300 mg IV infusion Q6W from Week 132 through Week 150 along with a single dose of natalizumab 300 mg SC injection or IV infusion as per participant's choice at Week 156. |
| Natalizumab | EXPERIMENTAL | Open-label natalizumab |
| Group 1 | EXPERIMENTAL | Adding natalizumab monthly infusion to Avonex weekly injection for up to 116 weeks. |
| Group 2 | PLACEBO_COMPARATOR | Adding placebo monthly infusion to Avonex weekly injection for up to 116 weeks. |
| Natalizumab with steroids | EXPERIMENTAL | For subjects whose GVHD assay is Ann Arbor score 2 or 3, the study treatment will consist of two drugs, prednisone (or methylprednisolone) and natalizumab. Protocol treatment must start within 3 days of the subject's diagnosis of acute GVHD. |
| Natalizumab 300 mg | EXPERIMENTAL | Participants will undergo a prospective baseline period of 6 weeks (Weeks -6 to 0) followed by placebo controlled phase to receive natalizumab 300 mg intravenous (IV) infusion every 4 weeks from Week 0 to Week 24. Participants will continue to receive natalizumab 300 mg IV infusion every 4 weeks for up to an additional 24 weeks in open label phase. |
| Placebo | PLACEBO_COMPARATOR | Participants will undergo a prospective baseline period of 6 weeks (Weeks -6 to 0) followed by placebo controlled phase to receive natalizumab matching placebo intravenous (IV) infusion every 4 weeks from Week 0 to Week 24. Participants will then receive natalizumab 300 mg IV infusion every 4 weeks for 24 weeks in open label phase. |
| natalizumab high dose | EXPERIMENTAL | Single IV (intravenous) dose natalizumab at baseline at one of two treatment windows, either within 9 hours of last known normal (LKN) or between 9-24 hours after LKN. |
| natalizumab low dose | EXPERIMENTAL | Single IV (intravenous) dose natalizumab at baseline at one of two treatment windows, either within 9 hours of last known normal (LKN) or between 9-24 hours after LKN. |
| Natalizumab 300 mg Intravenous (IV) Every 4 Weeks | ACTIVE_COMPARATOR | Natalizumab 300 mg IV every 4 weeks for 60 weeks. Open-label natalizumab treatment 300 mg IV at Weeks 60, 64, and 68. |
| Natalizumab 300 mg Subcutaneous (SC) Every 4 Weeks | EXPERIMENTAL | Natalizumab 300 mg SC every 4 weeks for 60 weeks. Open-label natalizumab treatment 300 mg IV at Weeks 60, 64, and 68. |
| Natalizumab 300 mg IV Every 12 Weeks | EXPERIMENTAL | Natalizumab 300 mg IV every 12 weeks for 60 weeks with matching IV placebo administered during the intervening 4-week periods. Open-label natalizumab treatment 300 mg IV at Weeks 60, 64, and 68. |
| Natalizumab 300 mg SC Every 12 Weeks | EXPERIMENTAL | Natalizumab 300 mg SC every 12 weeks for 60 weeks with matching SC placebo administered during the intervening 4-week periods. Open-label natalizumab treatment 300 mg IV at Weeks 60, 64, and 68. |
| Natalizumab 150 mg IV Every 12 Weeks | EXPERIMENTAL | Natalizumab 150 mg IV every 12 weeks for 60 weeks with matching IV placebo administered during the intervening 4-week periods. Open-label natalizumab treatment 300 mg IV at Weeks 60, 64, and 68. |
| Natalizumab 150 mg SC Every 12 Weeks | EXPERIMENTAL | Natalizumab 150 mg SC every 12 weeks for 60 weeks with matching SC placebo administered during the intervening 4-week periods. Open-label natalizumab treatment 300 mg IV at Weeks 60, 64, and 68. |
| Double-blind Natalizumab 300 mg | EXPERIMENTAL | 300 mg IV infusions of natalizumab over 60 minutes every 4 weeks for 20 weeks |
| Double-blind Placebo | PLACEBO_COMPARATOR | IV infusions of placebo over 60 minutes every 4 weeks for 20 weeks |
| Open-label Natalizumab | EXPERIMENTAL | 300 mg IV infusions of natalizumab over 60 minutes every 4 weeks for 20 weeks |
| IV placebo | PLACEBO_COMPARATOR | - |
| interferon β-1a, glatiramer acetate, or methylprednisolone | ACTIVE_COMPARATOR | - |
| 1 | EXPERIMENTAL | Natalizumab IV (Participants with secondary progressive multiple sclerosis) |
| 2 | EXPERIMENTAL | Natalizumab IM (Participants with secondary progressive multiple sclerosis) |
| 3 | EXPERIMENTAL | Natalizumab SC (Participants with secondary progressive multiple sclerosis) |
| 4 | OTHER | Standard of care as determined by the Investigator and Treating Neurologist (Participants with secondary progressive multiple sclerosis) |
| 5 | EXPERIMENTAL | Natalizumab SC (Participants with relapsing forms of multiple sclerosis) |
| 6 | EXPERIMENTAL | Natalizumab IV (Participants with relapsing forms of multiple sclerosis) |
| Name | Type | Description |
|---|---|---|
| Natalizumab | DRUG | Natalizumab 300 mg IV infusion. |
| Placebo | DRUG | Placebo monthly infusion for up to 116 weeks. |
| steroids | DRUG | Prednisone 2mg/kg/d (or methyl-prednisolone IV equivalent) |
| Methylprednisolone | DRUG | - |
| natalizumab IV | DRUG | natalizumab for IV Infusion |
| natalizumab SC | DRUG | natalizumab for Subcutaneous Injection |
| IV Placebo | DRUG | Intravenous placebo to natalizumab |
| SC Placebo | DRUG | Subcutaneous placebo to natalizumab |
| Natalizumab (BG00002) | DRUG | - |
| interferon beta 1-a | DRUG | 30 ug intramuscular once per week |
| glatiramer acetate | DRUG | 20 mg subcutaneous once daily |
| standard of care | OTHER | standard of care as determined by the Investigator and Treating Neurologist |
Key Inclusion Criteria: For Part 1: * Ability of the participant to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use confidential health information in accordance with national and local participant privacy regulations. * Diagnosi...
Natalizumab is being studied for multiple sclerosis, including relapsing-remitting multiple sclerosis and primary progressive multiple sclerosis, as well as graft versus host disease. It is also being investigated in clinical trials for acute ischemic stroke and focal epilepsy. Natalizumab is an investigational therapy and is not approved for these uses.
Natalizumab is a small molecule that targets alpha-4 integrin, a protein involved in immune cell migration. By binding to this target, it is thought to reduce the movement of immune cells into the central nervous system, which is relevant to its study in multiple sclerosis and other neurological conditions.
Natalizumab is being developed by Biogen Inc., a biotechnology company traded on the NASDAQ under the ticker symbol BIIB. Biogen is conducting clinical research on natalizumab across multiple indications, including multiple sclerosis and other neurological disorders.
Natalizumab is in Phase 2 clinical development. It has completed five clinical trials, including Phase 2 studies in acute ischemic stroke and focal epilepsy. Natalizumab is an investigational drug and has not been approved by regulatory authorities for the indications being studied.
Natalizumab has completed several clinical trials, including NCT01955707 and NCT02730455 for acute ischemic stroke, NCT03283371 for focal epilepsy, and NCT00424788 for relapsing forms of multiple sclerosis. These trials were randomized, double-blind, and placebo-controlled, with a total enrollment of 2795 participants.
Natalizumab is the same as Tysabri, a brand name for the drug. Tysabri is an established treatment for relapsing forms of multiple sclerosis. In ongoing research, natalizumab is being evaluated for additional conditions such as primary progressive multiple sclerosis and graft versus host disease.