Eculizumab For Acute Attack of Neuromyelitis Optica Spectrum Disorder

Eculizumab For Acute Attack of Neuromyelitis Optica Spectrum Disorder (NMOSD): a Multi-Center, Phase 2, Open Label Trial (EASE-NMO)

Neuromyelitis optica spectrum disorder (NMOSD) is a relapsing, inflammatory autoimmune disorder of the central nervous system characterized by the pathogenic anti-aquaporin 4 antibody (AQP4-IgG). The objectives of this study are to assess the efficacy and safety of eculizumab for treatment of patients with neuromyelitis optica spectrum disorders during acute phase who are anti-aquaporin-4 (AQP4) antibody-positive. Eculizumab, a humanized monoclonal antibody, inhibits the terminal complement protein C5 and prevents its cleavage into C5a and the formation of C5b-9 (MAC), has approved for preventive treatment of NMOSD. Given the high efficacy of C5 inhibition, eculizumab is proposed to potentially provide rapid relief from astrocyte destruction by reducing MAC formation, which could contribute to the fast alleviation of neurological deficit during NMO acute attack. The potential of eculizumab warrants further investigation as a treatment for acute neuromyelitis optica spectrum disorders attacks.

Inclusion criteria:

1. Anti-AQP4 antibody seropositive.

2. Male or female patients ≥18 years old

3. Body weight ≥ 35 kg

4. Leukocyte and CRP in the normal range

5. Acute optic neuritis and/or transverse myelitis presenting to the hospital within 10 days of symptom onset. An acute CNS inflammatory attack is defined as:

   • An acute presentation of neurological symptoms evolving over the course of 4 hours to 21 days that i. Localize to the spinal cord such as weakness, numbness or bowel/bladder dysfunction; or ii. Localize to the optic nerve with loss of visual acuity

   • Associated with a change in neurological exam that meet the following thresholds: i. Spinal cord lesions must show a reduction in 1 point on the EDSS scale from baseline; or a reduction of 0.5 if baseline EDSS is at least 5.5.

   ii. Optic nerve lesions must show a reduction in visual acuity by at least 2 lines on the vision chart.

   • Also associated with any of the following objective findings: i. New gadolinium-enhancing MRI lesion in the area of the CNS that correlates with the exam findings, or ii. Cerebrospinal fluid findings of pleocytosis with at least 10 WBC per microliter, or iii. Swelling of the optic nerve head on fundoscopy or swelling of the retinal nerve fiber layer by OCT of at least 25 microns from baseline.

6. A female subject is eligible to enter the trial if she is:

   • Not pregnant or nursing;

   • Of non-childbearing potential (i.e. women who have had a hysterectomy, are post-menopausal, which is defined as >2 years without menses or, in female subjects who have been post-menopausal for <2 years, must be confirmed with Follicle Stimulating Hormone (FSH) and estradiol levels), have both ovaries surgically removed or have current documented tubal ligation) OR

   • Of child-bearing potential (i.e. women with functional ovaries and no documented impairment of oviductal or uterine function that would cause sterility). This category includes women with oligomenorrhoea (even severe), women who are perimenopausal or have just begun to menstruate.

   • Subject has a negative serum pregnancy test at screening and agrees to one of the following:

     i. Complete abstinence from intercourse for the period from consent to trial until 6. months after the last dose of investigational product; or, ii. Consistent and correct use of one of the following acceptable methods of birth control for the period from consent into the trial until 6 months after the last dose of investigational product: i.Oral contraceptives (either combined or progesterone only) ii. Injectable progesterone iii. Levonorgestrel implants iv. Estrogenic vaginal ring v. Percutaneous contraceptive patches vi.Intrauterine device (IUD) or intrauterine system (IUS) with a documented failure rate of <1% per year vii.Male partner sterilization (vasectomy with documentation of azoospermia) prior to the female subject's entry into the trial; this male must be the sole partner for the subject viii.Double barrier method: condom and an occlusive cap (diaphragm or cervical/vault caps) with a vaginal spermicidal agent (foam/gel/film/cream/suppository).

Exclusion criteria:

1. Current evidence or known history of clinically significant infection including:

   • Chronic or ongoing active infectious disease requiring long term systemic treatment such as, but not limited to: PML, chronic renal infection, chronic chest infection with bronchiectasis, tuberculosis, or active hepatitis C
   • Previous serious opportunistic or atypical infections
   • History of positive serology for hepatitis B (unless history of vaccination)
   • Prior history, or suspicion, of tuberculosis (TB)
   • History of positive serology for HIV
   • Past or current history of medically significant adverse effects (including allergic reactions) from: Corticosteroids / Eculizumab

2. Current malignancy or history of malignancy in remission within the past 5 years, except for

   • Cervical carcinoma Stage 1B or less
   • Non-invasive basal cell and squamous cell skin carcinoma
   • Cancer diagnoses with a duration of complete response (remission) >5 years

3. Significant concurrent, uncontrolled medical condition including, but not limited to, cardiac, renal, hepatic, hematological, gastrointestinal, endocrine, immunodeficiency syndrome, pulmonary, cerebral, psychiatric, or neurological disease which could affect the subject's safety, impair the subject's reliable participation in the trial, impair the evaluation of endpoints, or necessitate the use of medication not allowed by the protocol, as determined by the principal investigator of the trial.

4. Use of an investigational drug or other experimental therapy within 4 weeks, 5 pharmacokinetic half-lives or duration of biological effect (whichever is longer) prior to screening.