Safety/tolerability of the anti-semaphorin 4D Antibody VX15/2503 in a randomized phase 1 trial

Abstract

Objective: To evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of VX15/2503 in a randomized, single-dose, dose-escalation, double-blind, placebo-controlled study enrolling adult patients with MS.

Methods: Single IV doses of VX15/2503 or placebo were administered. Ten patients each were randomized (4:1 randomization ratio) into 5 ascending dose cohorts of 1, 3, 6, 10, or 20 mg/kg. Safety, immunogenicity, PK/PD, MRI, ECG, and lymphocyte subset levels were evaluated. A Dose Escalation Safety Committee (DESC) approved each dose escalation.

Results: VX15/2503 was well tolerated, and all participants completed the study. Antibody treatment-related adverse events were primarily grade 1 or 2 and included urinary tract infection (12.5%) and muscle weakness, contusion, and insomnia (each 7.5%). No dose-limiting toxicities were observed, and no maximum tolerated dose was determined. One subject (20 mg/kg) experienced disease relapse 3 months before study entry and exhibited a grade 3 (nonserious) increase in brain lesions by day 29, possibly related to VX15/2503. Twenty-nine patients exhibited human anti-humanized antibody responses; 5 with titer ≥100. No anti-VX15/2503 antibody responses were fully neutralizing. VX15/2503 C_max, area under the time-concentration curve, and mean half-life increased with dose level; at 20 mg/kg, the T_1/2 was 20 days. Cellular SEMA4D saturation occurred at serum antibody concentrations ≤0.3 μg/mL, resulting in decreased cSEMA4D expression. At 20 mg/kg, cSEMA4D saturation persisted for ≥155 days. Total sSEMA4D levels increased with dose level and declined with antibody clearance.

Conclusions: These results support the continued investigation of VX15/2503 in neurodegenerative diseases.

Clinicaltrialsgov identifier: NCT01764737.

Classification of evidence: This study provides Class III evidence that anti-semaphorin 4D antibody VX15/2503 at various doses was safe and well tolerated vs placebo, although an increase in treatment-emergent adverse events in the treatment group could not be excluded (risk difference -0.7%, 95% CI -28.0% to 32.7%).

Figure 1. Disposition of study participants enrolled in the single ascending dose phase 1 study of VX15/2503

This flow diagram depicts the disposition of the participants in this single-dose, dose-escalation study of intravenously administered VX15/2503. Forty participants were treated with VX15/2503 and 10 with placebo; none discontinued the study. The median infusion time for all patients was 60 minutes, with durations ranging from 45 to 170 minutes.

Figure 2. Semi-log plot of mean VX15/2503 serum concentrations vs time after a single infusion

Mean serum VX15/2503 concentrations are shown vs scheduled sampling days. Data shown are for antibody-treated patients in each of the 5 dose cohorts; samples from placebo-treated subjects were assayed but not reported because of the absence of antibody in these samples. Sampling times were end of infusion, 4 and 8 hours on days 1 2, 4, 8, 15, 29, 43, 57, 71, 85, 155, and 190; time points beyond day 29 were successively applied to cohorts 2 through 5. Data shown represent mean values ± SD. Serum assays were performed in triplicate using a validated method.^,

Figure 3. Mean percent cellular SEMA4D saturation vs time after VX15/2503 administration

Percent VX15/2503 saturation of cSEMA4D on peripheral T lymphocytes is shown for antibody-treated participants in each dose cohort. The scheduled sampling times for each dose cohort were as described in the legend of figure 2. Data shown represent mean values ± SE; flow cytometric assays were performed in triplicate and data analyzed as previously described.^, T-cell saturation values below 20% were considered unsaturated; mean predose saturation values ranged between 0.7% and 18%.