Ublituximab versus Teriflunomide in Relapsing Multiple Sclerosis.

BACKGROUND: The monoclonal antibody ublituximab enhances antibody-dependent cellular cytolysis and produces B-cell depletion. Ublituximab is being evaluated for the treatment of relapsing multiple sclerosis. METHODS: In two identical, phase 3, double-blind, double-dummy trials (ULTIMATE I and II), participants with relapsing multiple sclerosis were randomly assigned in a 1:1 ratio to receive intravenous ublituximab (150 mg on day 1, followed by 450 mg on day 15 and at weeks 24, 48, and 72) and oral placebo or oral teriflunomide (14 mg once daily) and intravenous placebo. The primary end point was the annualized relapse rate. Secondary end points included the number of gadolinium-enhancing lesions on magnetic resonance imaging (MRI) by 96 weeks and worsening of disability. RESULTS: A total of 549 participants were enrolled in the ULTIMATE I trial, and 545 were enrolled in the ULTIMATE II trial; the median follow-up was 95 weeks. In the ULTIMATE I trial, the annualized relapse rate was 0.08 with ublituximab and 0.19 with teriflunomide (rate ratio, 0.41; 95% confidence interval [CI], 0.27 to 0.62; P<0.001); in the ULTIMATE II trial, the annualized relapse rate was 0.09 and 0.18, respectively (rate ratio, 0.51; 95% CI, 0.33 to 0.78; P = 0.002). The mean number of gadolinium-enhancing lesions was 0.02 in the ublituximab group and 0.49 in the teriflunomide group (rate ratio, 0.03; 95% CI, 0.02 to 0.06; P<0.001) in the ULTIMATE I trial and 0.01 and 0.25, respectively (rate ratio, 0.04; 95% CI, 0.02 to 0.06; P<0.001), in the ULTIMATE II trial. In the pooled analysis of the two trials, 5.2% of the participants in the ublituximab group and 5.9% in the teriflunomide group had worsening of disability at 12 weeks (hazard ratio, 0.84; 95% CI, 0.50 to 1.41; P = 0.51). Infusion-related reactions occurred in 47.7% of the participants in the ublituximab group. Serious infections occurred in 5.0% in the ublituximab group and in 2.9% in the teriflunomide group. CONCLUSIONS: Among participants with relapsing multiple sclerosis, ublituximab resulted in lower annualized relapse rates and fewer brain lesions on MRI than teriflunomide over a period of 96 weeks but did not result in a significantly lower risk of worsening of disability. Ublituximab was associated with infusion-related reactions. (Funded by TG Therapeutics; ULTIMATE I and II ClinicalTrials.gov numbers, NCT03277261 and NCT03277248.).

A phase 2 multicenter study of ublituximab, a novel glycoengineered anti-CD20 monoclonal antibody, in patients with relapsing forms of multiple sclerosis.

BACKGROUND: Ublituximab, a novel monoclonal antibody (mAb) targeting a unique epitope on the CD20 antigen, is glycoengineered for enhanced B-cell targeting through antibody-dependent cellular cytotoxicity (ADCC). Greater ADCC may allow lower doses and shorter infusion times versus other anti-CD20 mAbs. OBJECTIVE: The objective was to determine optimal dose, infusion time, and activity of ublituximab in relapsing multiple sclerosis. METHODS: This is a phase 2, placebo-controlled study. Patients received three ublituximab infusions (150 mg over 1-4 hours on day 1 and 450-600 mg over 1-3 hours on day 15 and week 24) in six dosing cohorts. The primary endpoint was B-cell depletion. RESULTS: In all cohorts (N = 48), median B-cell depletion was >99% by week 4, maintained at weeks 24 and 48. Most common adverse events (AEs) were infusion-related reactions (all grade 1-2), with no apparent increased incidence at shorter infusion times. There were no AE-related discontinuations. At weeks 24 and 48, no T1 gadolinium-enhancing lesions (p = 0.003) and a 10.6% decrease in T2 lesion volume (p = 0.002) were detected. The annualized relapse rate was 0.07; 93% remained relapse free on study. Overall, 74% of patients had no evidence of disease activity (NEDA). CONCLUSION: Ublituximab was safely infused as rapid as 1 hour, producing robust B-cell depletion and profound reductions in magnetic resonance imaging (MRI) activity and relapses.

Gonadal steroid regulation of renal injury in renal wrap hypertension.

Renal injury is greater in male compared with female rats after renal wrap (RW) hypertension. We investigated the role of gonadal steroids in the sex differences in RW disease severity in male (M) and female (F), castrated (Cast), and ovariectomized (OVX) rats and after dihydrotestosterone (DHT) and 17beta-estradiol (E2) treatment. Male castration attenuated the severity of RW-induced glomerulosclerosis (GS) [GS index (GSI): RW-M, 2.1 +/- 0.2; RW-Cast, 1.3 +/- 0.2; RW-Cast+DHT, 2.4 +/- 0.4], mean glomerular volume (MGV; microm3 x 10(6): RW-M, 1.9 +/- 0.1; RW-Cast, 1.45 +/- 0.15; RW-Cast+DHT, 1.91 +/- 0.15), tubular damage, and proteinuria (mg/day: RW-M, 130 +/- 8; RW-Cast, 105 +/- 5; RW-Cast+DHT, 142 +/- 9), whereas DHT treatment abrogated these effects. Ovariectomy increased the GSI (RW-F, 0.69 +/- 0.05; RW-OVX, 1.2 +/- 0.1; RW-OVX+E2, 0.65 +/- 0.05), tubular damage, and MGV (microm3 x 10(6): RW-F, 1.0 +/- 0.06; RW-OVX, 1.5 +/- 0.05; RW-OVX+E2, 0.96 +/- 0.06), whereas E2 treatment prevented these effects. Furthermore, DHT treatment of RW-OVX animals exacerbated the GSI (1.9 +/- 0.19), MGV (1.7 +/- 0.2 x 10(6) microm3), and proteinuria (171 +/- 21 mg/day) even further. Our data show that the lack of E2 and presence of androgens contribute to progressive renal disease induced by RW hypertension, suggesting that gonadal steroid status is an independent factor in the greater susceptibility men exhibit toward hypertension-associated renal disease compared with women.