Sep. 18, 2012

Rontalizumab: A Potential New Lupus Therapy

Safety and pharmacodynamic results of rontalizumab in a phase I, placebo controlled, double blind, dose escalation study in systemic lupus erythematosus
McBride JM, Jiang J, Abbas AR, Morimoto A, Li J, Maciuca R, Townsend M, Wallace DJ, Kennedy WP, and Drappa J. Arthritis & Rheumatism. 2012 Jul 25. doi: 10.1002/art.34632. [Epub ahead of print]

What is the topic?

Research over the last several years has found that in some patients with lupus, there is increased production of interferon-alpha. This molecule activates some genes which control the production of inflammatory proteins. This so-called “interferon signature” has been considered, therefore, a potentially modifiable pathway in the efforts to treat lupus. Rontalizumab is such a drug and may benefit people with lupus.

What did the researchers hope to learn?

The researchers hoped to learn about the safety and tolerability (a Phase I study) of rontalizumab in people with mild lupus disease activity.

Who was studied?

People with lupus between the ages of 18-65 participated in the study. These patients had anti-nuclear, anti-double-stranded DNA and/or anti-Smith antibodies.

How was the study conducted?

Exclusion criteria were as follows: organ-specific or life-threatening manifestations of lupus, severe infections, chronic viral infections, and taking either immune-suppressing drugs or more than 20 mg/day of prednisone (or equivalent).

The effects of single and repeated doses of rontalizumab (ranging from 0.3 – 10 mg/kg of body weight, either intravenously or subcutaneously) were evaluated. Patients were followed from 14 – 265 days after initial rontalizumab exposure. Patients were allowed to continue taking background medications, including non-steroidal anti-inflammatory drugs, anti-malarial drugs, and steroids (up to 20 mg/day of prednisone or equivalent).

At specific times throughout the study, the researchers collected blood from the study participants. Circulating levels of rontalizumab, RNA, proteins, and autoantibodies were examined with appropriate laboratory techniques.

What did the researchers find?

Most of the patients included in the study (n=60) were Caucasian (but African-Americans were included too) females. They were, on average, 47 years old, and had lupus for an average of nine years. Only 30% of the patients were taking prednisone upon entry to the study.

The five most commonly reported adverse events were upper respiratory infections, nausea and vomiting, headaches, musculoskeletal and connective tissue signs and symptoms, and urinary tract infections. The rates and incidence of infection-related adverse events were similar across groups of people receiving different doses of rontalizumab. No adverse events led to discontinuation of rontalizumab. Most adverse events were mild or moderate.

Serious adverse events, which did not differ significantly by group, included the following: musculoskeletal chest pain, abdominal pain of unknown cause, appendicitis, high-grade coronary artery stenosis, cerebral atherosclerosis, atrial fibrillation, and appendicitis.

About half of the study participants expressed an “interferon signature” in the blood (i.e., the blood contained an abundance of genes whose levels are known to be regulated by circulating levels of interferon). Of the many genes comprising the interferon signature, seven were chosen for further testing and were found to be representative of the whole. All seven of the interferon-regulated genes showed a significant reduction with either single or repeated doses of rontalizumab. During a subsequent drug-free period, the interferon-regulated genes returned to their initial levels. The higher the doses of rontalizumab that were administered, the greater the decline in interferon-regulated genes. In the highest dose group, this decline was maintained even up to 100 days after receiving the last dose of drug. Six months after receiving the last of the repeated doses of rontalizumab, interferon-regulated genes returned to their initial levels.

Despite these effects, rontalizumab did not induce a decline in levels of interferon-regulated proteins, and had no effects on levels of anti-double-stranded DNA antibodies.

What were the limitations of the study?

This study included a small number of lupus patients and rare side effects can only be ruled out in much larger studies. Also, the study was conducted in people with mild lupus disease activity. While the study showed that rontalizumab has the intended effect on the interferon-regulated genes in people with lupus, the drug seems to have limited effects on clinical symptoms of lupus.

What do the results mean for you?

This Phase I clinical trial showed that rontalizumab is safe for people with mild lupus and is effective in reducing interferon-regulated genes which play an important role in lupus. Rontalizumab is now being tested in Phase II clinical trials, in people with more severe lupus disease activity, to further evaluate the relationship between the drug, interferon-regulated genes, and clinical indicators of responsiveness to drug therapy.

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