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

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

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)

This study is a multicentre, double-blind, randomised, comparative Phase I study

The clinical study includes the following periods:

1. Screening period: days [-27…-0] (up to 1st administration of study therapy)

2. Main period: weeks [1-49]

   Patients who meet the eligibility criteria shall be randomised in a 1: 1 ratio to one of two study arms: RPH-035 and Ocrevus®

   During the Main Period, the patients will receive their first infusion of ocrelizumab (RPH-035 or Ocrevus®) at a dose of 300 mg, followed by another 300 mg of the drug product after 2 weeks. The duration of ocrelizumab administration will be 2.5 hours ± 15 minutes. The third infusion at a dose of 600 mg should be administered 6 months after the first infusion of the initial dose. The administration is scheduled for the "Week 25" visit.

   The Main Period includes regular collection of data on complaints and symptoms, physical examination, assessment of vital signs (measurement of body temperature, blood pressure (BP), pulse), body weight measurement, monitoring of laboratory parameters (clinical and biochemical blood tests, measurement of the concentration of immunoglobulin type G (IgG), general urine analysis), IG analysis, electrocardiogram (ECG), magnetic resonance imaging (MRI) at weeks 9, 17, 25, 49, neurological examination, assessment according to the Expanded Disability Status Scale (EDSS), registration of adverse events/serious adverse events (AEs/SAEs). MRI and assessment of response to therapy within the Main Period will be performed approximately once every 8 weeks during the first six months of the study (week 1 - week 25), then at week 49

   The week 49 visit consists of two stages: prior to drug administration, procedures are performed to assess the safety and effectiveness of the blinded therapy. After receiving and analysing the results, the research physician decides whether to terminate or extend therapy. If therapy needs to be continued, the patient is transferred to the follow-up period

3. After-Therapy period: weeks [49-97]

   During the After-Therapy Period, beginning at week 49, all patients will receive RPH-035 therapy, including those who received Ocrevus® therapy during the Main Period. Visits are also included in this period, which are conducted in the form of telephone contacts to assess the patient's well-being, collect data on concomitant therapy and possible AEs

   During the After-Therapy Period, patients will receive an IV infusion of ocrelizumab (RPH-035) at a dose of 600 mg at "Week 49", "Week 73", and "Week 97" visits

4. Follow-up period (FU)

The first follow-up visit (FU) is performed 28 ± 3 days after the last visit (scheduled or unscheduled)

• For patients who have completed their participation in the Main Period as planned and are not included in the After-Therapy Period, the FU visit will be conducted once 28 ± 3 days after day 337
• For patients who completed therapy early before day 337 in the study due to treatment failure, the first FU visit will be conducted 28 ± 3 days after the last visit conducted within the therapy (scheduled or unscheduled), but within 337 days. Further FU visits will be conducted in the form of telephone contacts with the patient/patient's relatives with a frequency of 1 time per 8 weeks (±7 days) until day 337 during the study or informed consent (IC) recall (whichever occurs first)
• If a patient completes therapy in the study early before day 337 of the study for a reason not related to treatment failure and is not prescribed another treatment regimen, FU visits will be conducted in the form of an assessment of the response to therapy with MRI once every 8 weeks ± 3 days (from the date of the first FU visit) until day 337 of the study or until another therapy is prescribed/IC is recalled (whichever occurs first). If another treatment regimen is prescribed, FU visits for these patients will continue at a frequency of once every 8 weeks (±7 days) until day 337 within the study or IC recall (whichever occurs first) in the form of telephone contacts with the patient/patient's relatives
• For patients who completed therapy during the after-therapy period either planned or early for any reason, 1 FU visit is scheduled 28 ± 3 days after the last visit during the after-therapy period. After this visit, the patient is considered to have completed the study

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, pneumonia) and gastroenteritis, as well as severe bacterial infections (e.g., meningitis, sepsis))
    2. any other acute or chronic diseases in the medical history that may affect the interpretation of the study results or pose an unacceptable risk to the patient when using the investigational therapy (in the Investigator's opinion)

18. One or more signs of depressed immune system function in the patient:

    1. serum IgG concentration < 4.0 g/L
    2. absolute CD4 + lymphocyte count < 0.25 × 10^9/L

19. Absence of IgG antibodies to Varicella zoster or a positive PCR reaction to herpes viruses of types 4, 5, 6

20. Positive result for any of the following tests: hepatitis B surface antigen (HBs Ag), hepatitis C virus antibodies (anti-HCV), human immunodeficiency virus antibodies 1 and 2 (anti-HIV1 and anti-HIV2 Ab), or a blood test for syphilis on screening

21. Presence of the following infections in a patient:

    1. infections that caused an increased body temperature above normal range or required the use of oral antibacterial and/or antiviral drugs within 4 weeks before randomisation, hospitalisation, or the use of parenteral anti-infective drugs within 2 months before randomisation (the exception is detection of asymptomatic herpes virus types 4, 5 and/or 6 on screening and their treatment within screening according to the study site's standards)
    2. confirmed SARS-CoV-2 coronavirus infection within 1 month before randomisation
    3. medical history of severe, recurrent, or chronic infections (including severe herpes infection, herpes zoster, sepsis, abscess, invasive fungal infections) in which, in the Investigator's opinion, the investigational medicinal product may cause harm to the patient
    4. medical history of active or latent tuberculosis, signs of tuberculosis infection based on the TB-feron test or Quantiferon test results and the chest X-ray performed during screening (it is possible to use the chest X-ray results performed no more than 2 months before the IC signing date)

22. Inability to administer the investigational medicinal product intravenously and to collect venous blood

23. Intolerance to oral or intravenous corticosteroids

24. Pregnancy, breastfeeding, and planning pregnancy during the period of participation in the study

25. Major surgeries (i.e., those involving opening of the abdominal cavity, chest cavity, skull) less than 60 days before the IC signing date (it is acceptable to include patients who have been fully recovered according to the Investigator's assessment), or the patient is scheduled to undergo major surgery during the period of participation in the study

26. Conditions that limit the patient's ability to comply with the protocol requirements, in the Investigator's opinion (e.g., medical history of dementia or mental disorders (including depression, schizophrenia), as well as information about drug or alcohol addiction within 12 months before the IC signing date, etc.)

27. Concurrent participation in other interventional clinical trials, participation in other clinical trials less than 30 days or less than 5 T1/2 of the investigational drugs before the IC signing date (provided the patient has received at least one administration of the investigational therapy), and previous participation in this clinical trial (provided the patient has received at least one administration of the investigational therapy)