The IMCY-MS-001 study is a study to test a new experimental drug, IMCY-0141, for the treatment of Relapsing-Remitting Multiple Sclerosis (RR-MS).

The pathophysiology of MS with known myelin autoantigens and T cell epitopes makes this disease a particularly attractive indication for development of an immunotherapeutic based on the Imcyse technology.

Based on the unique mechanism of action of the drug, IMCY-0141 administered as early as possible after confirmation of the diagnosis may potentially switch-off the autoimmune process and limit the corresponding myelin destruction. Newly (recently) diagnosed patients will be targeted to tackle the disease at its onset.

Before launching any efficacy studies, safety of IMCY-0141 in MS patients must be evaluated with a phase I, open-label, dose escalation clinical trial to evaluate the safety of three IMCY-0141 doses followed by a phase II, double-blind, randomized study with an adaptive design to determine if any IMCY-0141 dose(s) offer superior efficacy relative to placebo and to assess immune responses and biomarker data as potential early predictors of efficacy of IMCY-0141 in adults presenting with RR-MS.

The Sample Size determined for this study is as follows:

Phase I:

A total of 12 patients (4 patients in each of 3 dose cohorts) are planned to be enrolled. The study sample size has been estimated as adequate to provide a reliable safety assessment of the tested doses. All primary, secondary and exploratory endpoints will be summarized by descriptive statistics (continuous variables) or frequency tables (categorical variables), by dose group and overall. Additional patients may be enrolled if requested by the IDMC (Independent Data Monitoring Committee).

Phase II:

The sample size estimation is based on the total cumulative number of CUAL observed on brain MRI scans from week 12 till week 36. The study sample size has been estimated as adequate to determine if any IMCY-0141 doses offer superior efficacy (as measured by CUAL) relative to placebo. Using the negative binomial model for CUAL, a maximum total of 150 patients are planned to be enrolled (including the 12 patients enrolled in phase I), with 30 patients randomized to each of five groups:

• Placebo
• IMCY-0141 dose 1
• IMCY-0141 dose 2
• IMCY-0141 dose 3
• DMF (open label)

During the adaptive design phase (Phase IIa), a minimum of 40 patients will be enrolled (with 8 patients randomized to each of five groups) and analyzed along with the 12 phase I patients as detailed here:

• Placebo: 8 patients
• IMCY-0141 dose 1: 8 patients + 4 phase I patients
• IMCY-0141 dose 2: 8 patients + 4 phase I patients
• IMCY-0141 dose 3: 8 patients + 4 phase I patients
• DMF (open label) : 8 patients

During the Phase IIb part, up to 98 additional patients will be enrolled in order to get up to 150 patients spread over the groups selected for Phase IIb, with a maximum 30 patients randomized to DMF. These sample sizes are sufficient to deliver Type I errors less than 5% in our chosen null scenarios, and unconditional powers greater than 75% and conditional powers greater than 90% in our two alternative scenarios.

Inclusion Criteria (Phase I and II):

1. Male or female between 18 and and 45 years old.

2. RR-MS according to the 2017 revisions of the McDonald Criteria.

3. Patients should be newly diagnosed or have a disease duration ≤ 3 years.

4. If not newly diagnosed, patients should have at least one documented clinical relapse in the last 12 months.

5. Patients should present with at least 1 Gadolinium-enhancing (Gd+) T1-weighted lesion OR at least 2 new or enlarging T2-weighted lesions at screening MRI compared to a reference scan in the last 6 months.

6. No background MS treatment at the time of study treatment start (refer to exclusion criteria for details about authorized washout period for some first line treatment).

7. EDSS ≤ 5.0 at screening.

8. Women of childbearing potential (1) should use an highly effective contraception method (2) from screening and for the whole duration of the study. (1) Of child-bearing potential is defined as being post onset of menarche and not meeting any of the following conditions:

   • Menopausal for at least 2 years (follicle-stimulating hormone within menopausal range),
   • Having undergone bilateral tubal ligation at least 1 year previously
   • Having undergone bilateral oophorectomy or hysterectomy. (2) HIGHLY EFFECTIVE contraceptive measures acceptable for the whole duration of the study have been defined based on the CTFGs recommendations on contraception and are the following:
   • Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal),
   • Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable).
   • Intrauterine device (IUD)
   • intrauterine hormone-releasing system (IUS)
   • Monogamous relationship with vasectomized partner. Partner must have been vasectomized for at least 6 months prior to the patient's entry into the study
   • Abstinence or absence of sexual relations with men.

9. Ability to understand and comply with research requirements and procedures, in opinion of investigator (Signed Informed Consent)

Exclusion Criteria (Phase I and II):

1. Secondary or primary progressive multiple sclerosis and late onset multiple sclerosis (LOMS).

2. Findings on brain MRI scan indicating any clinically significant brain abnormality like:

   • Doubts about MS diagnosis (based on clinically or imaging abnormalities)
   • PML cases (positive PML checklist according to "suspected PML case adjudication instructions")
   • Co-morbidities influencing the MS disease evolution (i.e. Tumor, large infarction, CSF obstruction)

3. Patient has complete transverse myelitis or bilateral optic neuritis.

4. Systemic corticosteroids or adrenocorticotropic hormone (ACTH) without chronic use within 30 days prior to screening MRI.

5. Treatment with rituximab, ocrelizumab, mitoxantrone, or lymphocyte depleting therapies (e.g., alemtuzumab, anti-CD4, cladribine, cyclophosphamide, total body irradiation, bone marrow transplantation) within 48 weeks prior to study treatment start.

6. Use of lymphocyte trafficking blockers (e.g., natalizumab, fingolimod) within 24 weeks prior to study treatment start.

7. Treatment with β-interferons or glatiramer acetate within 4 weeks prior to study treatment start.

8. Treatment with teriflunomide within 12 weeks prior to study treatment start.

9. Exposure to dimethyl fumarate within 6 months prior to study treatment start.

10. Any investigational drug within the past 6 months at the time of study treatment start.

11. Immunosuppressive therapy including chronic use of systemic steroids in past year. Topical, inhalational or intranasal corticosteroids are allowed.

12. Primary or secondary immune deficiency disorders with the exception of well-controlled diabetes or thyroid disorder.

13. Patients with combined other auto-immune or inflammatory disorders.

14. Have signs or symptoms of active or long COVID infection or a positive COVID PCR test during the screening period. In the case of PCR positivity, a reswabbing will be done. If reswabbing returns a negative result, the initiation of study treatment can occur.

15. Have evidence of current or past human immunodeficiency virus (HIV-1 and 2), Hepatitis B or Hepatitis C infection: HBsAg+ or anti-HBc+; anti-HCV+ (unless the polymerase chain reaction [PCR] for HBV DNA (hepatitis B) or HCV RNA (hepatitis C) is negative according to local procedure).

16. Current signs or symptoms of infection at time of study treatment start or within 2 weeks prior to planned administration of the study product or intravenous antibiotics within 2 months prior to the first planned administration of the study product.

17. Live, attenuated vaccine within 3 months prior to the first planned administration of the study product.

18. Inability to comply with MRI scanning, including contraindications to MRI such as known allergy to gadolinium contrast media, claustrophobia, presence of a pacemaker, cochlear implants, ferromagnetic devices or clips, intracranial vascular clips, insulin pumps, nerve stimulators.

19. Any other significant disease, disorder or finding which may significantly increase the risk to the patient because of participation in the study, affect the ability of the patient to participate in the study or impair interpretation of the study data.

20. Patients with a known hypersensitivity to any component of the drug product.

21. Patients with psychiatric or cognitive disorders.

22. History of MS related seizures not adequately controlled by medications.

23. History of cancer, except adequately treated basal cell or squamous cell carcinoma of the skin (no more than 3 lesions requiring treatment in lifetime) or carcinoma in situ/cervical intraepithelial neoplasia of the uterine cervix, unless considered cured > 5 years

24. Abnormal renal function defined by creatinine clearance ≤ 60 ml/min/1.73m2.

25. Patient with total lymphocytes count < 1000/mm3.

26. Patient with abnormal hepatic function defined as any liver enzyme > 3 ULN, bilirubin > 3 ULN with exception of Gilbert Syndrome.

27. Breastfeeding/lactating or pregnant women.

Exclusion Criteria specific for Phase I:

1. Patient HLA DRB1*03:01 positive

Exclusion Criteria specific for Phase II:

1. Patients already included in Phase I

This is a two-step study with a phase I, open-label, dose escalation clinical trial to evaluate the safety of three IMCY-0141 doses followed by a phase II, double-blind, randomized study with an adaptive design to determine if any IMCY-0141 doses offer superior efficacy relative to placebo.