Inclusion Criteria:

• Ability of the subject or his/her legally authorized representative (e.g., parent or legal guardian) 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 subject privacy regulations.
• Aged 18 to 75 years, inclusive, at the time of informed consent or subject meets the minimum age of consent in accordance with national regulations (whichever is higher).
• Must have focal epilepsy diagnosed on clinical grounds and as applicable supported by electroencephalogram findings [Scheffer 2017] and brain imaging. Subjects with multifocal epilepsy may be included if all other entry criteria are met.
• Must have a drug-resistant epilepsy defined as failure of adequate trials of 2 (or more) tolerated and appropriately chosen and used AEDs (whether as monotherapies or in combination) [Kwan 2010].
• Must have had a MRI scan of the brain within 48 months of the Screening Visit (Week -6) to assist in the electroclinical assessment of a structural etiology for focal epilepsy. For subjects not meeting this criterion, an MRI may be obtained within the prospective baseline period. Subjects without an MRI of the brain within 48 months prior to screening and with an absolute contraindication to MRI will be considered on a case-by-case basis (see Table 1).
• Must have confirmation of diagnosis of drug-resistant focal epilepsy by a member of the IERC [Section 19.2.2]. The independent reviewer will also adjudicate the presence or absence of a structural etiology for focal epilepsy. Appropriate diagnostic information must be sent to the reviewer as soon as possible after the Screening Visit (Week -6) but preferably should not be less than 2 weeks prior to randomization.
• The study will aim to include approximately 28 subjects with a structural etiology for focal epilepsy and approximately 28 subjects with a high seizure frequency (≥24 seizures during the 6-week prospective baseline period), and these are not mutually exclusive.
• Experiences 6 or more seizures during the 6-week prospective baseline period and is not seizure free for more than 21 consecutive days during the prospective baseline period.
• Seizures included in counts are focal aware seizures (previously termed “simple partial seizures”) with motor signs, focal impaired awareness seizures (previously termed “complex partial seizures”), and focal to bilateral tonic-clonic seizures (previously termed “partial onset with secondary generalization”). Focal aware seizures without motor signs will not be included.
• Stable regimen of 1 to 5 AEDs. Stable is defined as no modification of AED dosing within 4 weeks prior to the Screening Visit (Week -6). Dosing regimen must also be stable throughout the 6-week prospective baseline period. Benzodiazepines used on a regular basis for any indication at stable dosing will be considered as an AED. As needed (PRN) benzodiazepine use for occasional seizure exacerbation is allowed and must be documented. PRN benzodiazepine use for any other indication (e.g., sleep or anxiety) must also be documented as such. PRN benzodiazepine use for any indication averaging more than twice weekly (more than 12 doses) during the 6-week prospective baseline period will be considered as an AED. Neurostimulation, including vagus nerve stimulation and the RNS System, is allowed and must be documented; however, implantation must have occurred at least 6 months prior to the Screening Visit (Week -6).
• Dosing parameters for neurostimulation must be stable for 4 weeks prior to enrollment and throughout the 6-week prospective baseline period. Prior epilepsy surgery is allowed; however, surgery must have occurred at least 6 months prior to the Screening Visit (Week -6). A ketogenic diet is allowed and must be documented; however, initiation must have occurred and the patient must be at a stable ratio at least 4 weeks prior to the Screening Visit (Week -6) and throughout the 6-week prospective baseline period.
• All women of childbearing potential and all men must practice highly effective contraception during the study and for at least 3 months after their last dose of study treatment. For further details of contraceptive requirements for this study, please refer to Section 15.5.

Exclusion Criteria:

Candidates will be excluded from study entry if any of the following exclusion criteria exist at the time of screening, or at the timepoint specified in the individual criterion listed, and must be reconfirmed at the time of randomization.

• Focal aware seizures without motor signs are the only seizure type.
• Diagnosis of generalized, combined generalized and focal, or unknown epilepsy [Scheffer 2017].
• Known progressive structural CNS lesion.
• History of seizures occurring in predominantly clustered patterns, as determined by the Investigator, over the 12 months prior to the Screening Visit (Week -6) or during the 6-week prospective baseline period, where individual seizures cannot be counted.
• History of status epilepticus within the previous 6 months.
• Known history or presence of non-epileptic seizures.
• Current major depressive episode, a positive report on the “baseline/screening” eC-SSRS at the Screening Visit (Week -6) or on the “since last visit” eC-SSRS at Week 0, or considered at risk of suicide or self-harm based on the clinical judgement of the Investigator (Section 14.1).
• Known planned epilepsy surgery or admission to the epilepsy monitoring unit with intended drug change within 12 months of Week 0.
• Any clinically significant medical condition that may contraindicate the use of natalizumab, impair reliable participation in the study, or necessitate the use of medication not allowed per protocol.
• Evidence of significant active hepatic disease including elevations of aspartate aminotransferase (AST) or alanine aminotransferase (ALT) above 3 times the upper limit of normal or bilirubin above 2 times the upper limit of normal.
• Evidence of significant active renal disease including creatinine above 2 times the upper limit of normal.
• Evidence of significant active hematologic disease including absolute neutrophil count (ANC) <1000 μL, platelet count <80,000, absolute lymphocyte count <800 cells/μL.
• Known history of positive test result for human immunodeficiency virus.
• Known history of positive test result for hepatitis C virus antibody or hepatitis B virus (defined as positive for hepatitis B surface antigen AND hepatitis B core antibody).
• Signs of active herpes simplex type 1 or 2 or varicella within 4 weeks prior to randomization.
• Symptoms of bacterial, fungal, or viral infection (including upper respiratory tract infection) within 14 days prior to randomization.
• A clinically significant infectious illness (e.g., cellulitis, abscess, pneumonia, septicemia, tuberculosis) within 3 months prior to randomization, or PML or other opportunistic infections at any time.
• Signs or symptoms suggestive of any ongoing serious infection, based on medical history, physical examination, or laboratory testing, as considered by the Investigator.
• Immunocompromised subjects as determined by the Investigator, based on medical history, physical examination, laboratory testing, or immunosuppressive or immunomodulating treatment. Immunosuppressive or immunomodulating treatment, including chronic oral or IV steroids, must be discontinued at least 4 weeks prior to screening.
• History of any clinically significant (as determined by the Investigator) cardiac, endocrinologic, hematologic, hepatic, immunologic, metabolic (including uncontrolled diabetes), urologic, pulmonary, neurologic, dermatologic, psychiatric, renal, or  other major disease that would preclude participation in a clinical study.
• History of malignant disease, including solid tumors and hematologic malignancies (with the exception of basal cell and squamous cell carcinomas of the skin that have been completely excised and are considered cured).
• History of transplantation or any antirejection therapy.
• History of drug or alcohol abuse (as defined by the Investigator) within 2 years prior to the Screening Visit (Week -6). Stable cannabinoid use is allowed if started at least 4 weeks prior to the Screening Visit (Week -6) and must be documented.
• Exposure to monoclonal antibodies, cytokines, growth factors, soluble receptors, other recombinant products, or fusion proteins within 6 months prior to the Screening Visit (Week -6).
• Women who are pregnant or breastfeeding, and women intending to become pregnant during the study.
• Prior exposure to natalizumab.
• Current enrollment or a plan to enroll in any interventional clinical study in which an investigational treatment or approved therapy for investigational use is administered within 6 months prior to the Screening Visit (Week -6).
• Inability to comply with study requirements including completing or updating seizure diary. Subjects missing more than 6 days of seizure diary data during the 6-week prospective baseline period cannot be randomized and will be considered as screen failures. Patients with limitations who are unable to complete the QOLIE-31, HADS-D, and/or SDMT are not excluded from the study; however, other study requirements must be completed. At the discretion of the Investigator, the C-SSRS may be completed in place of the eC-SSRS in these patients.
• Subjects with modification of AEDs during the 6-week prospective baseline period cannot be randomized and will be considered as screen failures.
• Other unspecified reasons that, in the opinion of the Investigator or Biogen, make the subject unsuitable for enrollment.