A Comparative Study of Pharmacokinetics, Pharmacodynamics, Safety, and Immunogenicity of RPH-035 and Ocrevus® in Patients With Relapsing-remitting or Secondary Progressive Multiple Sclerosis With Exacerbations

Treatment tested

• Ocrelizumab

  B-lymphocyte antigen CD20 binding agent

Compared with

• Ocrelizumab

  B-lymphocyte antigen CD20 binding agent

Other measures (14)

Patients shall meet all of the following inclusion criteria: 1. Availability of the voluntarily signed and dated patient Informed Consent (IC) form for participation in this study 2. Multiple sclerosis with exacerbations (relapsing-remitting multiple sclerosis (RRMS) or secondary progressive multiple sclerosis (SPMS) with exacerbations) according to the McDonald diagnostic criteria as revised in 2017, with symptoms lasting at least 1 year before signing the IC form 3. The patient's medical history includes the use of ≤ 3 prior multiple sclerosis disease modifying drugs (DMT) 4. The patient has one of the following signs of disease activity: 1. ≥ 2 documented disease exacerbations in the previous 24 months before the IC signing date 2. ≥ 1 documented disease exacerbation in the previous 12 months before the IC signing date 3. 1 documented exacerbation in the previous 24 months before the IC signing date and ≥ 1 documented brain lesion on the contrast-enhanced Magnetic Resonance Imaging (MRI) scan in the previous 6 months before the IC signing date 5. Expanded Disability Status Scale (EDSS) index is 0-5.5 points inclusively on screening 6. No Multiple sclerosis (MS) exacerbations within 30 days before the IC signing date and throughout the entire screening examination 7. Ability, in the Investigator's opinion, to comply with the Protocol procedures and requirements 8. Negative pregnancy test for female participants with preserved reproductive potential 9. Consent of the patient with preserved reproductive potential to abstain from heterosexual contacts or to use reliable contraceptive methods, starting from the moment of the IC form signing, throughout the entire treatment period within the study, as well as for 12 months after the last ocrelizumab administration. Female participants are considered infertile if definitive amenorrhea was determined (from patient's words) retrospectively after 12 months of natural amenorrhea, i.e amenorrhea with an appropriate clinical status, such as a suitable age (between 45 and 55 years ) Patients cannot be included in the study if they meet at least one of the following exclusion criteria: 1. Medical history of hypersensitivity to monoclonal antibody drugs or to any component of the investigational medicinal products 2. Prior therapy with ocrelizumab 3. Primary progressive multiple sclerosis or SPMS without exacerbations 4. Contraindications for MRI, including intolerance to Gd-containing contrast agents and claustrophobia 5. Medical history of other neurological diseases (excluding migraines) or first diagnosed on screening, including but not limited to the following: 1. ischemic cerebrovascular disorders (e.g., stroke, transient ischemic attack) or spinal cord ischemia 2. malignant and benign central nervous system (CNS) tumours (meningiomas, gliomas, etc.) requiring surgical intervention 3. potential metabolic causes of myelopathy, identified from the medical history or in patient words (untreated vitamin B12 deficiency, etc.) 4. infectious myelopathy (syphilis, Lyme disease, human T-lymphotropic virus 1 [HTLV-1], herpes zoster) 5. hereditary progressive CNS degenerative disorder, MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, stroke) 6. neuromyelitis optical spectrum disorders 7. progressive multifocal leukoencephalopathy 6. Systemic autoimmune disease (lupus, rheumatoid arthritis, antiphospholipid antibody syndrome, Sjorgen's syndrome, Behcet's syndrome) 7. Sarcoidosis 8. Medical history of severe, clinically significant brain or spinal cord injury (brain contusion, spinal cord compression) 9. Medical history of the patient includes the following therapy: 1. targeted biological B-cell therapy (ocrelizumab, rituximab or ofatumumab, etc.) 2. bone marrow transplantation, lymphocyte irradiation 3. any unregistered biological drug product for MS treatment 10. The patient received any of the following therapies (subject to the time/dose restrictions specified): 1. natalizumab (inclusion of such patients in the study is allowed, provided that the therapy was completed > 12 months before the IC signing date) 2. fampridine (administration is allowed, provided only that the patient has been receiving continuous therapy with the drug product for at least 3 months before the IC signing date) 3. alemtuzumab (\< 4 years before the IC signing date) 4. fingolimod (\< 6 weeks before the IC signing date) 5. dimethyl fumarate, siponimod (\< 4 before the IC signing date) 6. teriflunomide (\< 3.5 months before the IC signing date), in case of accelerated elimination procedure \< 2 weeks before the IC signing date) 7. immunosuppressive drug products: azathioprine, mycophenolate mofetil, methotrexate, TNF-α inhibitors (\< 6 months before the IC signing date) cyclophosphamide, mitoxantrone, cladribine (\< 24 months before the IC signing date) 8. interferon beta/glatiramer acetate (\< 2 weeks before the IC signing date) 9. immunoglobulin intravenous administration within \< 12 weeks before the IC signing date 10. plasmapheresis or plasma adsorption (\< 21 days before the randomisation date) 11. therapy with systemic glucocorticosteroids (GCS), adrenocorticotropic hormones (ACTH) \< 1 month before MRI screening 12. live or live attenuated vaccine within \< 3 months before the IC signing date or vaccination plans for the study period 11. Concomitant diseases that increase the patient's risk of AE development during the use of the investigational therapy or may affect the assessment of MS symptoms severity; mask, intensify, modify MS symptoms or cause clinical and laboratory-instrumental symptoms similar to those in MS as confirmed by primary documentation data: 1. uncontrolled arterial hypertension characterised by systolic blood pressure (BP) above 150 mmHg or diastolic BP above 90 mmHg during the antihypertensive therapy 2. medical history of moderate or severe heart failure (functional class III/IV according to the New York Heart Association (NYHA) classification), stable effort angina of functional class III-IV, unstable effort angina, or medical history of myocardial infarction less than 6 months before randomisation 3. diagnosis of any clinically significant (in the opinion of the investigator) respiratory disease including, but not limited to, chronic obstructive pulmonary disease of grade 3 or 4 severity 4. diagnosis of active liver disease or liver failure based on medical history 12. Haematological disorders: 1. haemoglobin \< 80 g/L 2. white blood cells (WBC) \< 3.0 × 10\^9/L 3. absolute neutrophil count \< 1.5 × 10\^9/L 4. absolute lymphocyte count \< 0.5 × 10\^9/L 5. platelets \< 100 × 10\^9/L 13. Renal impairment: a. creatinine > 1.5 × upper limit of normal (ULN) or glomerular filtration rate \< 45 mL/min, calculated using CKD-EPI formula 14. Hepatic impairment: a. bilirubin, aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) ≥ 2 × ULN 15. Presence of oncological pathology that is progressing or requires anti-tumour therapy (including hormonal therapy) within 5 years before the IC signing date, except for radically resected cervical carcinoma in situ or radically resected basal cell/squamous-cell carcinoma of skin 16. Medical history of diverticulitis or other gastrointestinal tract (GI) disorders (e.g., inflammatory bowel disease, mechanical ileus, hernia) that can cause gastrointestinal (GI) perforations in patients 17. Diseases (e.g., asthma, psoriasis) that require treatment with immunosuppressive biological drugs or systemic corticosteroids during the study 1. medical history of primary and/or secondary immunodeficiencies (most commonly manifested by recurrent severe infections that are refractory to the standard treatment, in typical cases, these include upper and lower respiratory tract infections (e.g., sinusitis, bronchitis, pne

The study goal is to establish the equivalence of pharmacokinetic (PK) properties, as well as the comparability of safety, immunogenicity (IG) and pharmacodynamics (PD) of the drug product RPH-035 (R-Pharm JSC, Russia) in comparison with the drug product Ocrevus® (F. Hoffmann-La Roche Ltd., Switzerland) when used in patients with multiple sclerosis (MS)