MADRID – Despite failing its phase II primary endpoint, the single-domain antibody vobarilizumab, being developed for rheumatoid arthritis, will advance to phase III studies.
A robust placebo response obscured the strength of clinical response to vobarilizumab, a nanobody that blocks the soluble interleukin-6 receptor, Thomas Dorner, MD, said at the European Congress of Rheumatology. But by 24 weeks of treatment, vobarilizumab effected a deep, sustained response in up to half of patients with rheumatoid arthritis who responded inadequately to methotrexate.
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The safety profile was encouraging, Dr. Dorner said, with just one case of gastrointestinal perforation. These events have been a problem in some IL-6 blockade studies; the protein stimulates repair of the intestinal epithelium and blocking it leaves the tissue vulnerable to injury. The single case in this trial occurred 17 days after the patient withdrew from the study for other reasons, so it was not considered to be related to the study medication, Dr. Dorner said.
Vobarilizumab is composed of two heavy chains, lacking the two light-chain arms of a full antibody. It is minuscule – just 10% of the molecular weight of a conventional antibody. One chain targets human serum albumin and is designed to prolong the molecule’s half-life by up to 14 days; the other chain targets the soluble IL-6 receptor.
The phase IIb study comprised 345 patients with active RA despite treatment with methotrexate (mean dose 16 mg/week). While staying on their methotrexate, they were equally assigned to five treatment groups: placebo or vobarilizumab at 75 mg every 4 weeks; 150 mg every 4 weeks; 150 mg every 2 weeks; or 225 mg every 2 weeks.
The primary endpoint was the difference in ACR20 response at week 12 between placebo and the four dosing groups. While the majority of patients taking vobarilizumab met that endpoint, the percentages did not significantly differ from each other, nor from placebo. ACR20 was met by 62% of the placebo group and 81%-72% of the vobarilizumab groups. ACR50 was met by 28% of the placebo group and 45%-29% of the vobarilizumab groups and ACR70 by 9% of the placebo group and 21%-14% of the vobarilizumab groups.
However, Dr. Dorner said, response in the placebo group tended to tail off as the study progressed, while staying significantly stronger in the higher-dose vobarilizumab groups. By week 24, 16% of the placebo group still had an ACR50 – significantly less than in the vobarilizumab 150 mg/2 weeks and 225 mg/2 weeks groups (31%, 39%, respectively).
On a measure of remission that combined C-reactive protein of less than 2.6 mg/L and low disease activity, vobarilizumab looked much better at week 24. At that point, 16% of placebo patients met the endpoint, compared to 39% of the 150 mg/4 weeks and 150 mg/2 weeks vobarilizumab groups, and 51% of the 225 mg/2 weeks group.
Adverse events occurred in 36% of placebo patients and about 44% of vobarilizumab patients and did not show any dose-response relationship. About 38% of these were considered treatment related; 7% of the cohort withdrew due to an adverse event. There were seven serious infections among those taking vobarilizumab (three pneumonia, and one each herpes zoster, ear infection, staphylococcus sepsis, and bacterial arthritis). One patient died of a myocardial infarction, but she had experienced a previous heart attack and undergone percutaneous coronary intervention. The single gastrointestinal perforation occurred in a woman taking the highest dose of vobarilizumab, more than 2 weeks after she stopped taking it.
Vobarilizumab will continue into a phase III study, according to the Ablynx website. The company is seeking an industry partner. AbbVie had an option to license vobarilizumab, but declined last fall on the mixed results of Ablynx’s phase II studies.
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