Open-label, Multi-center, Phase I/II Study to Assess Safety, Disease Progression and Cellular Kinetics Following YTB323 Administration in Participants With Non-active Progressive Multiple Sclerosis (PMS)

An Open-label, Multi-center, Phase I/II Study to Assess Safety, Disease Progression, and Cellular Kinetics Following YTB323 Administration in Participants With Non-active Progressive Multiple Sclerosis (PMS)

This is an open-label, multi-center, non-confirmatory study to assess the safety, disease progression, and cellular kinetics following YTB323 administration to 28 participants with non-active Progressive Multiple Sclerosis (PMS). The study design utilizes an ascending single dose design consisting of 3 sentinel cohorts followed by an expansion cohort.

Study Overview

• Status: Recruiting
• Conditions: Progressive Multiple Sclerosis
• Intervention / Treatment: Biological: rapcabtagene autoleucel (YTB323)

Detailed Description

All participants in this study will receive YTB323. Both the participant and the study doctor will know the participant is getting YTB323. Participants will be given one dose of YTB323. Different groups of participants may receive a higher dose of YTB323, if proven to be safe for every participant at the lower dose. Participants are in this study for 2 years and will be followed for an additional 13 years in a long-term follow up study. The main question this trial is designed to answer: Is YTB323 treatment safe for participants with progressive MS?

• Study Type: Interventional
• Enrollment (Estimated): 28
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Novartis Pharmaceuticals; Phone Number: +41613241111; Email: novartis.email@novartis.com
• Study Contact Backup: Name: Novartis Pharmaceuticals

Study Locations

• Australia
  • New South Wales
    • Darlinghurst, New South Wales, Australia, 2010
      • Recruiting
      • Novartis Investigative Site
  • Victoria
    • Melbourne, Victoria, Australia, 3004
      • Recruiting
      • Novartis Investigative Site
• Canada
  • Quebec
    • Québec, Quebec, Canada, G1J 1Z4
      • Recruiting
      • Novartis Investigative Site
• France
  • Bron, France, 69677
    • Recruiting
    • Novartis Investigative Site
  • Montpellier, France, 34090
    • Recruiting
    • Novartis Investigative Site
  • Nancy, France, 54035
    • Recruiting
    • Novartis Investigative Site
  • Rennes, France, 35033
    • Recruiting
    • Novartis Investigative Site
• Germany
  • Essen, Germany, 45147
    • Recruiting
    • Novartis Investigative Site
  • Ulm, Germany, 89081
    • Recruiting
    • Novartis Investigative Site
• Italy
  • GE
    • Genova, GE, Italy, 16132
      • Recruiting
      • Novartis Investigative Site
  • MI
    • Milan, MI, Italy, 20132
      • Recruiting
      • Novartis Investigative Site
• Spain
  • Málaga, Spain, 29010
    • Recruiting
    • Novartis Investigative Site
  • Catalonia
    • Barcelona, Catalonia, Spain, 08035
      • Recruiting
      • Novartis Investigative Site
  • Madrid
    • Majadahonda, Madrid, Spain, 28222
      • Recruiting
      • Novartis Investigative Site
• Switzerland
  • Bern, Switzerland, 3010
    • Active, not recruiting
    • Novartis Investigative Site
  • Lausanne, Switzerland, 1011
    • Recruiting
    • Novartis Investigative Site
  • Zurich, Switzerland, 8091
    • Recruiting
    • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

1. Male or female participants 18 to 60 years (inclusive) at screening.
2. Signed informed consent must be obtained prior to participation in the study.

3. Able to communicate well with the investigator, to understand and comply with the requirements of the study including:

   • Able to undergo lumbar puncture (LP), blood draws, tolerate brain and spinal MRI, and able to participate and tolerate all study procedures at study visits.
4. Diagnosis of SPMS or PPMS according to the 2017 McDonald diagnostic criteria (Thompson et al 2018) as confirmed at screening visit.
5. Less than 15 years (inclusive) from onset of first MS symptoms as determined by the investigator during screening.
6. Ambulatory Patients (EDSS 3 to 6.5 inclusive) at screening.
7. Evidence of recent (within 24 months) disease progression of ≥1.00 on the EDSS scale.
8. No relapse in the last 24 months at screening.
9. No Gd-enhancing lesion on brain or spinal cord MRI at screening.
10. Participants must receive or be current on all recommended vaccinations according to institutional, local, or global guidelines for immunocompromised patients at least 6 weeks prior to lymphodepletion.

Key Exclusion Criteria:

1. Diagnosis of relapsing multiple sclerosis (RMS) or active PMS according to the 2017 revision of the McDonald diagnostic criteria (Thompson et al 2018) at screening.
2. History of, or current, clinically significant CNS disease except MS (e.g. stroke, traumatic brain or spinal injury, history or presence of myelopathy, history of seizures or epilepsy) or neurological disorders which may mimic MS at screening.
3. Evidence of clinically significant cardiovascular (such as but not limited to myocardial infarction, unstable ischemic heart disease, New York Heart Association Class III/IV left ventricular failure, arrhythmia and uncontrolled hypertension within 6 months prior to or during screening).
4. Participants with history of confirmed Progressive Multifocal Leukoencephalopathy (PML) or neurological symptoms consistent with PML prior to or during screening.
5. Clinically significant, active, opportunistic, chronic or recurrent infection (including positive for hepatitis B or hepatitis C) confirmed by clinical evidence, imaging, or positive laboratory tests one month prior to leukapheresis.
6. Have donated blood or experienced a loss of blood > 400 mL within 3 months prior screening, or longer if required by local regulations.
7. Any prior stem cell therapy or organ transplantation or gene therapy.

8. Any contraindications to LP, including but not limited to:

   • Known or suspected structural abnormality of the lumbar spine that, in the opinion of the Investigator, may interfere with the performance of the LP, or increase the risk of the procedure for the participant.
   • Presence of risk for increased or uncontrolled bleeding (including but not limited to vascular abnormalities or neoplasms at or near the LP site, disorders of the coagulation cascade, platelet function, or platelet count).
   • Participants on anticoagulants (e.g., warfarin) or antiplatelets [except for low-dose aspirin (100 mg/day or lower) and low-dose nonsteroidal anti-inflammatory drugs such as ibuprofen (600 mg/day or lower) which are allowed], are not eligible to participate.
9. Not willing or able to have MRI scans as per protocol e.g. due to claustrophobia, or absolute contraindications to MRI (e.g., metallic implants, metallic foreign bodies, pacemaker, defibrillator).
10. Pregnant or nursing (lactating) women.
11. Past surgical history of splenectomy.
12. Evidence of active or latent tuberculosis (TB) infection by QuantiFERON® TB-Gold assay (or equivalent) performed at Screening by central lab. In case of unclear or indeterminate test results, the Investigator should consult with an infectious disease expert to exclude the diagnosis of active or latent TB infection and document this in the source data. Participant should be excluded if they have any signs of active TB observed in available lung imaging (e.g., X-ray or HRCT).
13. Any psychiatric, pulmonary (including, history of or active severe respiratory disease, including Chronic Obstructive Pulmonary Disease, interstitial lung disease or pulmonary fibrosis), renal, hepatic, endocrine, metabolic (e.g. severe hypoproteinemia due to nephrotic syndrome), hematological disorders or gastrointestinal disease that, in the investigator's opinion, would compromise the safety of the participant, interfere with the interpretation of the study results or otherwise preclude participation or protocol adherence of the participant, prior to or during screening.
14. Grade 2 or higher thromboembolic event in the past 4 weeks prior to or during Screening or evidence of disorders of coagulation or platelet function including subjects that require chronic use of anticoagulation or antiplatelet drugs (please refer to the key exclusion criteria no. 8 for the exceptions).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: YTB323 Cohort 1; Participants will receive one dose of YTB323	Biological: rapcabtagene autoleucel (YTB323); CAR-T cell suspension for intravenous infusion
Experimental: YTB323 Cohort 2; Participants will receive one dose of YTB323	Biological: rapcabtagene autoleucel (YTB323); CAR-T cell suspension for intravenous infusion
Experimental: YTB323 Cohort 3; Participants will receive one dose of YTB323	Biological: rapcabtagene autoleucel (YTB323); CAR-T cell suspension for intravenous infusion
Experimental: YTB323 Cohort 4; Participants will receive one dose of YTB323	Biological: rapcabtagene autoleucel (YTB323); CAR-T cell suspension for intravenous infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants with dose limiting toxicities (DLTs), Adverse Events (AEs), and Serious Adverse Events (SAEs)	Occurrence, severity, and frequency of dose limiting toxicities (DLTs), AEs and SAEs, including changes in vital signs, electrocardiograms (ECGs), laboratory parameters, neurological status and magnetic resonance (MRI) of the brain and spinal cord qualifying and reported as AEs.	Day 1 through Year 2

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Measure of Disability: Expanded Disability Status Scale (EDSS).	EDSS is used to measure the change in disability level in participants using a scale from 0 to 10. The higher the score, the greater the degree of disability.	Day 1 through Year 2
Measure of Disability: Short Form Health Survey (SF-36 v2)	The Short Form Health Survey (SF-36 v2) is a widely used and extensively studied instrument to measure health-related quality of life among healthy participants and participants with acute and chronic conditions. It consists of eight subscales that can be scored individually: Physical Functioning, Role-Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role-Emotional, and Mental Health. Two overall summary scores, the Physical Component Summary (PCS) and the Mental Component Summary (MCS) also can be computed. The SF 36 has proven useful in monitoring general and specific populations, comparing the relative burden of different diseases, differentiating the health benefits produced by different treatments, and in screening individual participants.	Day 1 through Year 2
Measure of Disability: Timed 25 Foot Walk (T25FW)	The T25FW is a mobility test based on a timed walk of 25 feet that is administered by a trained administrator. The participant is directed to walk the clearly marked 25-foot distance as quickly as possible. Longer completion time corresponds with decreased mobility.	Day 1 through Year 2
Measure of Disability: 9 Hole Peg Test (9HPT)	The 9HPT is a finger dexterity test that is administered by a trained administrator. The participant is directed to put 9 pegs, one by one, onto and then off the holder board as quickly as possible starting with using only the dominant hand, and then repeated with the non-dominant hand. Longer completion times are associated with decreased finger dexterity.	Day 1 through Year 2
Measure of Disability: Symbol Digit Modalities Test (SDMT)	The SDMT is a timed cognition test administered by a trained administrator. The test assesses sustained attention, processing speed, visual scanning, and motor speed to determine cognitive impairment. Participants are given a coding key which contains abstract symbols that correspond to specific numbers. Participants are timed how quickly and accurately they are able to substitute the symbols for the numbers and is scored by the number of correctly coded items.	Day 1 through Year 2
Humoral Immunogenicity of YTB323	Incidence and prevalence of pre-existing and treatment induced humoral immunogenicity of YTB323	Day 1 through Year 2
Cellular Immunogenicity of YTB323	Incidence and prevalence of pre-existing and treatment induced cellular immunogenicity of YTB323	Day 1 through Year 2
Modified Fatigue Impact Scale (MFIS)	The MFIS is a questionnaire to assess fatigue-related symptoms in patients with MS.	Day 1 through Year 2
Whole Blood Pharmacokinetics (PK) of YTB323 - CMAX	Measured by Cmax - The maximum plasma concentration of YTB323	Day 1 through Year 2
Whole Blood Pharmacokinetics (PK) of YTB323 - AUC	Measured by AUC - Area under the curve of YTB323	Day 1 Through Year 2
Whole Blood Pharmacokinetics (PK) of YTB323 - Tmax	Measured by Tmax - Time to Reach the Maximum Concentration After Drug Administration of YTB323	Day 1 Through Year 2
Whole Blood Pharmacokinetics (PK) of YTB323 - Clast	Clast is defined as the Last observed (quantifiable) plasma concentration (Clast	Day 1 Through Year 2
Whole Blood Pharmacokinetics (PK) of YTB323 - Tlast	Tlast is defined as Time of Last Measurable Concentration	Day 1 through Year 2
Safety data including dose limiting toxicities (DLTs), Adverse Events (AEs), and Serious Adverse Events (SAEs) from each dose level	Safety data from each dose level will be used to assess safe dose-level(s) to be continued in phase 2 and later clinical studies	Day 1 through Year 2

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): December 12, 2024
• Primary Completion (Estimated): June 14, 2030
• Study Completion (Estimated): June 14, 2030

Study Registration Dates

• First Submitted: November 4, 2024
• First Submitted That Met QC Criteria: November 4, 2024
• First Posted (Actual): November 5, 2024

Study Record Updates

• Last Update Posted (Actual): November 20, 2025
• Last Update Submitted That Met QC Criteria: November 17, 2025
• Last Verified: November 1, 2025

More Information

Terms related to this study

• Keywords: Multiple Sclerosis; MS; CAR-T; PMS; Progressive Multiple Sclerosis; Chimeric Antigen Receptor T cells; YTB323; rapcabtagene autoleucel
• Additional Relevant MeSH Terms: Nervous System Diseases; Pathologic Processes; Chronic Disease; Disease Attributes; Autoimmune Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Pathological Conditions, Signs and Symptoms; Multiple Sclerosis; Multiple Sclerosis, Chronic Progressive
• Other Study ID Numbers: CYTB323r12101

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No