Phase 1 Trials of Gatralimab, a Next-Generation Humanized Anti-CD52 Monoclonal Antibody, in Participants with Progressive Multiple Sclerosis

Abstract

Introduction: Lymphocyte depletion via anti-CD52 monoclonal antibody (mAb) therapy is an effective treatment strategy for relapsing-remitting multiple sclerosis (MS) but is associated with infusion/injection-associated reactions (IARs) and autoimmune-related adverse events (AEs). Gatralimab is a next-generation humanized anti-CD52 mAb.

Methods: Two first-in-human trials were conducted in participants with progressive MS to assess the pharmacodynamics, pharmacokinetics, and safety of gatralimab administered via subcutaneous (SC) and intravenous (IV) routes, and to determine the effect of different comedication regimes on IARs to SC gatralimab. A Phase 1 trial (NCT02282826) included double-blind, placebo-controlled sequential ascending single IV (1, 3.5, and 12 mg) and SC (12, 36, and 60 mg) dose groups. A Phase 1b trial (NCT02977533) involved five groups who received SC gatralimab (36, 48, or 60 mg) and different comedications. A long-term safety (LTS) study (NCT02313285) examined safety and pharmacodynamics over 4 years.

Results: Gatralimab produced depletion of lymphocytes (dose-dependently) and CD4+ regulatory T cells, with partial repopulation to normal values by approximately 12 months. Peak serum gatralimab concentrations followed dose-proportionality and were delayed by 6.0-7.5 days following SC administration. Treatment-emergent AEs, including IARs, were reported for most participants but were generally of mild or moderate severity, and treatment-emergent serious AEs were mostly MS-related. Methylprednisolone and antihistamine comedications were associated with reduced incidence of fevers and skin and subcutaneous tissue AEs, respectively. During the LTS study, one participant (3.0%) experienced an autoimmune-related AE (Basedow's disease), and subsequently died from pulmonary sepsis deemed unrelated to gatralimab by the investigator.

Conclusions: These data show that gatralimab achieves the desired pharmacodynamic effect of lymphocyte depletion followed by repopulation, and has an acceptable safety profile, including low risk of non-MS autoimmunity. Although gatralimab is no longer in development for MS, insights from these trials may inform the development of comedication regimes of future anti-CD52 mAbs and subcutaneous formulations of other lymphocyte-depleting mAbs.

Trial registration: NCT02282826, NCT02977533, NCT02313285.

Keywords: Clinical trial; Disease-modifying therapies; Multiple sclerosis; Progressive; Treatment response.

Fig. 1

Study design. A Phase 1. B Phase 1b. Phase 1 participants administered ≥ 12 mg of gatralimab received comedication as described in the Materials and Methods section. For cohort 1A, naproxen was administered pre-dose on D1 and every 12 h on D1 and 2. For cohort 1B, methylprednisolone was administered 24 h and 30 min pre-dose. For cohort 1C, methylprednisolone was administered 24 h and 30 min pre-dose and 24 h post-dose. For cohort 1D, methylprednisolone was administered as per cohort 1C when given alone or for two additional days (D3 and 4) when given with antihistamines. For cohort 2E, methylprednisolone was administered 24 h and 30 min pre-dose and every 24 h on D2–4 with no taper (640 mg total). Ranitidine, levocetirizine, and fexofenadine were administered once daily from D1 to D7. Fexofenadine was administered twice daily in cohort 2E if exanthema occurred. n indicates the number of participants in each group. *When sufficient pharmacological activity was demonstrated, the dose level was repeated IV in an additional 8 participants. Otherwise, dose escalation proceeded via IV administration. **After review of the pharmacologically active IV dose level (n = 12), transition to SC administration occurred.^#Premedication determined after completion of cohort 1c. ^##Premedication determined after SDRM. D day, IV intravenous, SC subcutaneous, SDRM Safety Data Review Meeting

Fig. 2

Mean absolute lymphocyte count during Phase 1 and 1b trials (cells/nL ± SD). A Phase 1 IV cohorts, B Phase 1 SC cohort, C Phase 1b SC cohort. Lower and upper limits of normal as provided by the clinical laboratory are indicated with solid gray lines. CS corticosteroid, D day, H hour, IB ibuprofen, IV intravenous, premed premedication, prophy prophylaxis, SC subcutaneous, SD standard deviation

Fig. 3

Mean absolute CD4+ Treg count during Phase 1 and 1b trials (cells/nL, ± SD). A Phase 1 IV cohorts, B Phase 1 SC cohort, C Phase 1b SC cohort. Lower and upper limits of normal as provided by the clinical laboratory are indicated with solid gray lines. CS corticosteroid, H hour, IB ibuprofen, IV intravenous, premed premedication, prophy prophylaxis, SC subcutaneous, SD standard deviation, Treg regulatory T cells

Fig. 4

Pharmacodynamics during the LTS study. A Mean absolute lymphocyte count (cells/nL ± SD), B Mean absolute CD4+ Treg cell count (cells/nL ± SD). Lower and upper limits of normal as provided by the clinical laboratory are indicated with solid gray lines. B baseline, SD standard deviation, Treg regulatory T cells