SAN DIEGO — Ublituximab, a novel glycol-engineered anti-CD20 antibody, demonstrated rapid and robust B cell depletion, a profound reduction in gadolinium (Gd)-enhancing lesions, and clinical stability at week 24 in a phase 2a study of patients with relapsing multiple sclerosis (MS).
Compared with other drugs in this class, ublituximab has a shorter infusion time and is expected to cost less, researchers reported at Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) 2018.
“We achieved B cell depletion handily — 99% reduction from baseline. In fact, we hit that mark, by and large, after the first 150-mg infusion,” said James L. Eubanks, PhD, director of field medical affairs for MS at TG Therapeutics. “We have seen no gadolinium-enhancing lesions in any of the subjects, and only one relapse has been confirmed in this cohort at 24 weeks.”
The study’s principal investigator was Edward Fox, MD, PhD, from Central Texas Neurology Consultants in Round Rock, Texas.
Potential Advantages
Ublituximab is a novel monoclonal antibody targeting a unique epitope on the CD20 antigen. It is glycol-engineered to enhance affinity for all variants of FcγRIIIa receptors, demonstrating greater antibody-dependent cellular cytotoxicity activity (ADCC) than rituximab and ofatumumab. In in vitro studies, ublituximab demonstrated 100 times greater natural killer cell–mediated ADCC than did rituximab.
In more than 800 patients with various B cell malignancies, ublituximab has shown “robust” activity and a favorable safety profile, according to the investigators. Two phase 3 trials in cancer are ongoing or completed in hematologic cancers.
For both the MS and cancer populations, the drug’s enhanced ADCC potency may offer a benefit over currently available anti-CD20s in terms of lower doses and shorter infusion times, the investigators noted on their poster. Another benefit may be seen in terms of cost, according to a company spokesperson.
Wendy Su, PhD, also from TG Therapeutics, told Medscape Medical News, “We’re obviously not the first anti-CD20 antibody, but we have advantages. We are reducing the infusion time, which ‘gives back the day’ to the patient and turns over the infusion chair faster in the clinic. And our chief executive officer says we are going to be very competitive with price. In fact, we will be significantly less expensive than ocrelizumab. We believe that providing a drug that’s more affordable is important.”
The phase 2a study reported at the third annual forum of Americas Committee for Research and Treatment of Multiple Sclerosis (ACTRIMS) assessed the efficacy, safety, and B cell depletion dynamics in patients with relapsing MS. The researchers reported preliminary safety and efficacy at 24 weeks.
The study is a 52-week placebo-controlled, multicenter study that has enrolled 40 patients with relapsing MS (Expanded Disability Status Scale [EDSS] score ≤ 5.5) to one of five dose cohorts. Most patients had been previously treated with a variety of disease-modifying therapies.
The doses used (150 mg on day 1, 450 to 600 mg on day 15, 450 to 600 mg at week 24) were lower, and infusion times faster, than those used with current anti-CD20 infused therapies (ie, 4 hours). On day 1, the infusion time was 2 to 4 hours, depending on cohort; on day 15, it was 1 to 3 hours; and at week 24, it was only 1 hour. All subsequent infusions after the first two, therefore, are 1 hour long.
The primary endpoint was responder rate, defined as percentage of patients with 95% or greater reduction in peripheral CD19+ B cells within 2 weeks after the second infusion (day 15).
At week 4, median B cell depletion was 99% from baseline in ublituximab-treated patients, maintained to week 24. “This validated our thinking in terms of the enhanced potency of this drug,” Dr Eubanks said. “With this finding, we moved to a phase 3 trial that is currently recruiting.”
MRI at week 24 revealed no T1 Gd-enhancing lesions in any patients, a 100% drop from a mean of 2.58 lesions at baseline (P = .0005). “Mechanistically, this is a known benefit of anti-CD20 antibodies, but you can’t get more profound than this,” he commented in an interview.
While cautioning that the follow-up was only 6 months, he reported that only one patient has experienced a relapse on treatment (2.5%), compared with 85% of patients who reported at least one relapse in the year prior.
Similarly, EDSS score was stable or improved. At baseline, the mean EDSS score was 2.3, dropping to 2.0 at week 24, an improvement of 0.30 (±1.0) points. For 78% of patients, EDSS score improved or remained stable, he reported.
NEDA in 74% of Patients
In 35 patients who completed all the assessments, 74% fulfilled the criteria for having no evidence of disease activity (NEDA). Within this assessment the following outcomes were achieved by week 24:
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97% were relapse-free;
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94% had no confirmed disability progression;
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91% had no evidence of clinical disease;
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83% had no evidence of MRI disease;
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100% had no T1 Gd-enhancing lesions; and
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83% had no new or enlarging T2 lesions.
No serious adverse events or clinically significant lab abnormalities have been observed. The most commonly reported side effect (40%) was infusion-related reactions, which were all grade 2 or less. Faster infusion times, as low as 1 hour for 450 mg, did not result in their increased frequency.
Coauthor Michael Racke, MD, professor of neurology at the Ohio State University, told Medscape Medical News that ublituximab could well have advantages from the patient perspective. For them, he said, faster infusion may be important.
He reiterated what the manufacturer has indicated regarding the future cost of the drug. “My understanding is that this drug will be priced lower than others,” he said. “This will also help patients.”
He noted that many other anti-CD20 antibodies are in trials or in development, meaning that patients should eventually have several options within this class of agents.
“Small Advantage”
But Bruce Cree, MD, PhD, clinical research director at the University of California MS Research Center, San Francisco, who was not involved in the study, questioned whether a shorter infusion time is that important, especially for a drug that is administered only twice a year.
“Unless you go to something that can be self-administered at home,” such as ofatumumab, he noted, “then a difference of a couple of hours, twice a year, is not an enormous advantage in my mind.”
But he did view the findings very positively, noting that “the data clearly show that ublituximab depletes B cells very efficiently.” Coming from an open-label study that lacks a comparator group, the data are hard to interpret with respect to clinical and radiographic endpoints, he said. “But still, the findings are going in the right direction, with a decrease in contrast-enhancing lesions and an increase in the number of patients not experiencing relapse, versus baseline,” he said.
TG Therapeutics sponsored the study. Dr Eubanks and Dr Su are employees of TG Therapeutics. Dr Racke and Dr Cree have disclosed no relevant financial relationships.
Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) 2018. Abstract P028. Presented February 1, 2018.
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