A Phase 2a Study of Foralumab Nasal in Patients With Multiple System Atrophy (MSA)

Official title

A Phase 2a Study to Evaluate Microglial Activation, Safety, and Clinical Effects of Foralumab Nasal in Patients With Multiple System Atrophy (MSA)

Overview

A Phase 2a Study of Foralumab Nasal in Patients with Multiple System Atrophy (MSA)

Interventions

• Drug Foralumab Nasal
  Foralumab is an anti-CD3 monoclonal antibody administered as a nasal spray. Participants will complete eight 3-week dosing cycles over the study. During each cycle, Foralumab will be administered intranasally three times per week for the first two weeks, with no administration in the third week.

Primary outcome measures

• Change from Screening to Month 6 in the total MDS-UMSARS score [Time frame: From Screening to Month 6]
• Change in TSPO activity as measured by [F-18]PBR06 retention calculated over whole brain and within key regions of interest (ROIs) at 6 months as compared to screening [Time frame: From Screening to Month 6]

Secondary outcome measures (9)

• Change from Screening to Month 6 in MDS-UMSARS Part III (motor examination) score [Time frame: From Screening to Month 6]
• Proportion of patients with ≥30% improvement in MDS-UMSARS total score at Month 6 [Time frame: From Screening to Month 6]
• Change from Screening to Month 6 in COMPASS-31 total score [Time frame: From Screening to Month 6]
• Change from Screening to Month 6 in MSA-QoL summary index score [Time frame: From Screening to Month 6]
• Percent whole brain volume change (PWBVC) between screening and 6 months [Time frame: From Screening to Month 6]
• Percent putamen volume change (PPVC) between screening and 6 months [Time frame: From Screening to Month 6]
• Percent cerebellar volume change (PCVC) between screening and 6 months [Time frame: From Screening to Month 6]
• Percent pontine volume change (PPoVC) between screening and 6 months [Time frame: From Screening to Month 6]
• Percent midbrain volume change (PMVC) between screening and 6 months [Time frame: From Screening to Month 6]

Eligibility criteria

Inclusion criteria

• Subjects with a clinical diagnosis of Clinically Established or Clinically Probable Multiple System Atrophy in accordance with 2022 MDS diagnostic criteria.
• Age 30 to 85 years, at the time of signing the informed consent.
• Stable dopaminergic treatment for at least 4 weeks before enrollment.
• Adequate hematologic parameters without ongoing transfusion support: Hemoglobin (Hb) ≥ 9 g/dL; Platelets ≥ 100 x 109 cells/L.
• Creatinine ≤ 1.5 x the upper limit of normal (ULN), or calculated creatinine clearance ≥ 60 mL/minute x 1.73 m2 per the Cockcroft-Gault formula.
• Total bilirubin ≤ 2 times the upper limit of normal (ULN) unless due to Gilbert's disease.
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 times ULN.
• QT interval corrected for rate (QTcF) ≤ 470 msec for women and ≤ 450 msec for men on the ECG obtained at Screening.
• Negative urine pregnancy test within 7 days prior to the first dose of study therapy for women of child-bearing potential (WCBP), defined as a sexually mature woman who has not undergone a hysterectomy or who has not been naturally postmenopausal for at least 24 consecutive months (i.e., who has had menses any time in the preceding 24 consecutive months). Sexually active WCBP and male patients must agree to use highly effective methods to avoid pregnancy (oral, injectable, or implantable hormonal contraceptive; tubal ligation; intra-uterine device; barrier contraceptive with spermicide; or vasectomized partner) throughout the study and for 90 days after the completion of study treatment.
• Patients whose immunizations are fully up to date at the Screening, according to the assessment of their primary care physician and neurologist.
• Ability to provide written informed consent.

Exclusion criteria

• Diagnosis or suspicion of other cause for Parkinsonism or a known alternate neurologic diagnosis.
• Female patient who is pregnant, lactating, breastfeeding, or planning to become pregnant during study.
• Individuals with claustrophobia who cannot tolerate the study procedures
• Non-MRI-compatible implanted devices.
• Low-affinity binders for translocator protein (TSPO) PET ligands.
• Systemic corticosteroid treatment in the past four weeks (excluding nasal or local treatment).
• Individuals with significant cognitive impairment (i.e., MoCA score less than or equal to 20).
• Brain MRI indicative of significant abnormalities that interfere with PET-MRI co-registration (i.e., large prior hemorrhage or multiple infarcts).
• Serious cardiac condition within the last 6 months, such as uncontrolled arrhythmia, myocardial infarction, unstable angina, or heart disease defined by the New York Heart Association (NYHA) Class III or Class IV or hereditary long QT syndrome.
• Concomitant medication(s) that may cause QTc prolongation or induce Torsades de Pointes, except for antimicrobials that are used as standard of care to prevent or treat infections and other such drugs that are considered by the Investigator to be essential for patient care.
• Patients who test positive for human immunodeficiency virus (HIV), hepatitis B virus surface antigen (HBsAg), hepatitis C virus (HCV) or positive Epstein-Barr virus (EBV) IgM at the Screening Visit.
• Past medical history of a hematologic or solid malignancy.
• Treatment with chronic immunosuppressives such as interferon, glatiramer acetate, fingolimod, Siponimod, dimethyl fumarate, or natalizumab within the past 90 days.
• Inability to tolerate nasally administered medications.
• Nasal corticosteroids, nasal antihistamines, nasal flu dosing within the past 30 days, or anticipated need during the study.
• Chronic rhinitis, deviated septum, nasal polyps, history of sinusitis treated within the past 8 months.
• Inflammatory bowel disease, rheumatoid arthritis, systemic lupus erythematosus, primary Sjögren's Syndrome, asthma, or type 1 diabetes.
• Neutropenia or an absolute neutrophil count of < 1,000 cells/mL or other indicators of severe immunosuppression.
• Severe lymphopenia or an absolute lymphocyte count of < 500 cells/mL
• Patients with a history of gadolinium allergy.
• A recent clinically significant active infection requiring treatment with antibiotics or other anti-infective agents within the past 15 days.
• Any other medical or surgical intervention or other condition which, in the opinion of the Principal Investigator, could compromise adherence to study requirements or confound the interpretation of study results.
• Unable or unwilling to comply with protocol requirements.
• Active COVID-19 disease.
• COVID-19 vaccine within past 10 days or any other vaccine within past 7 days (at dosing).

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 1 center

• Brigham and Women's Hospital — Boston

Publications

• Wenning GK, Stankovic I, Vignatelli L, Fanciulli A, Calandra-Buonaura G, Seppi K, Palma JA, Meissner WG, Krismer F, Berg D, Cortelli P, Freeman R, Halliday G, Hoglinger G, Lang A, Ling H, Litvan I, Low P, Miki Y, Panicker J, Pellecchia MT, Quinn N, Sakakibara R, Stamelou M, Tolosa E, Tsuji S, Warner T, Poewe W, Kaufmann H. The Movement Disorder Society Criteria for the Diagnosis of Multiple System PMID 35445419
• Singhal T, Cicero S, Rissanen E, Ficke J, Kukreja P, Vaquerano S, Glanz B, Dubey S, Sticka W, Seaver K, Kijewski M, Callen AM, Chu R, Carter K, Silbersweig D, Chitnis T, Bakshi R, Weiner HL. Glial Activity Load on PET Reveals Persistent "Smoldering" Inflammation in MS Despite Disease-Modifying Treatment: 18 F-PBR06 Study. Clin Nucl Med. 2024 Jun 1;49(6):491-499. doi: 10.1097/RLU.0000000000005201. PMID 38630948
• Singhal T, O'Connor K, Dubey S, Pan H, Chu R, Hurwitz S, Cicero S, Tauhid S, Silbersweig D, Stern E, Kijewski M, DiCarli M, Weiner HL, Bakshi R. Gray matter microglial activation in relapsing vs progressive MS: A [F-18]PBR06-PET study. Neurol Neuroimmunol Neuroinflamm. 2019 Jul 1;6(5):e587. doi: 10.1212/NXI.0000000000000587. eCollection 2019 Sep. PMID 31355321
• Shahnawaz M, Mukherjee A, Pritzkow S, Mendez N, Rabadia P, Liu X, Hu B, Schmeichel A, Singer W, Wu G, Tsai AL, Shirani H, Nilsson KPR, Low PA, Soto C. Discriminating alpha-synuclein strains in Parkinson's disease and multiple system atrophy. Nature. 2020 Feb;578(7794):273-277. doi: 10.1038/s41586-020-1984-7. Epub 2020 Feb 5. PMID 32025029
• Owen DR, Yeo AJ, Gunn RN, Song K, Wadsworth G, Lewis A, Rhodes C, Pulford DJ, Bennacef I, Parker CA, StJean PL, Cardon LR, Mooser VE, Matthews PM, Rabiner EA, Rubio JP. An 18-kDa translocator protein (TSPO) polymorphism explains differences in binding affinity of the PET radioligand PBR28. J Cereb Blood Flow Metab. 2012 Jan;32(1):1-5. doi: 10.1038/jcbfm.2011.147. Epub 2011 Oct 19. PMID 22008728
• Ndayisaba A, Pitaro AT, Willett AS, Jones KA, de Gusmao CM, Olsen AL, Kim J, Rissanen E, Woods JK, Srinivasan SR, Nagy A, Nagy A, Mesidor M, Cicero S, Patel V, Oakley DH, Tuncali I, Taglieri-Noble K, Clark EC, Paulson J, Krolewski RC, Ho GP, Hung AY, Wills AM, Hayes MT, Macmore JP, Warren L, Bower PG, Langer CB, Kellerman LR, Humphreys CW, Glanz BI, Dielubanza EJ, Frosch MP, Freeman RL, Gibbons CH PMID 36190676
• Moreira TG, Matos KTF, De Paula GS, Santana TMM, Da Mata RG, Pansera FC, Cortina AS, Spinola MG, Baecher-Allan CM, Keppeke GD, Jacob J, Palejwala V, Chen K, Izzy S, Healey BC, Rezende RM, Dedivitis RA, Shailubhai K, Weiner HL. Nasal Administration of Anti-CD3 Monoclonal Antibody (Foralumab) Reduces Lung Inflammation and Blood Inflammatory Biomarkers in Mild to Moderate COVID-19 Patients: A Pilot S PMID 34475873
• Meissner WG, Remy P, Giordana C, Maltete D, Derkinderen P, Houeto JL, Anheim M, Benatru I, Boraud T, Brefel-Courbon C, Carriere N, Catala H, Colin O, Corvol JC, Damier P, Dellapina E, Devos D, Drapier S, Fabbri M, Ferrier V, Foubert-Samier A, Frismand-Kryloff S, Georget A, Germain C, Grimaldi S, Hardy C, Hopes L, Krystkowiak P, Laurens B, Lefaucheur R, Mariani LL, Marques A, Marse C, Ory-Magne F, PMID 38598572

Identifiers

NCT: NCT06868628 · TILS-025

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗