Dec. 22, 2009

Genentech’s Rontalizumab Is Well-Tolerated by Lupus Patients in a Phase I Clinical Trial

Jacqueline M McBride Ph.D., Alyssa Morimoto Ph.D, Jorn Drappa M.D.

Genentech Inc, 1 DNA Way, South San Francisco, CA

What was the objective of this study?

New treatments for lupus have to undergo a series of clinical trials to test whether they are safe and effective before the FDA can approve them for general use in patients. This trial was the first stage of testing for rontalizumab, which is a new treatment that interferes with an inflammatory protein called "interferon-alpha." Interferon-alpha is increased in many people with lupus, so it is thought that maybe this kind of treatment might work for lupus. The first stage of testing, called Phase I, is focused mostly on testing the safety of new treatments. Phase I studies are kind of like dipping your toe in the water and typically involve small numbers of patient volunteers. If the treatment seems safe enough after Phase I, then larger studies can be done to see if the treatment would help to treat the symptoms of lupus.

What is IFN-alpha and what is its role in lupus?

Interferons are a group of small proteins produced by the body as part of the immune response that helps defend against bacteria and viruses. Research over the last several years has found that in some patients with lupus, there is increased interferon, especially a type called interferon-alpha. Also interferon-alpha causes some genes to be used as blueprints for making inflammatory proteins. It turns out that these genes are "expressed" (meaning they have gone through the first step in the protein-making process) at far higher levels in the white blood cells of lupus patients compared to healthy people. This very pattern of "expression" of interferon-regulated genes in lupus is often referred to as the "interferon signature." Of course, interferon-alpha is important in the immune response, as it is very important in fighting off viruses, for example. But maybe patients with lupus have too much of a good thing. This has led to the idea of trying to neutralize some of the excessive interferon-alpha that drives chronic inflammation and autoimmunity in lupus.

What is rontalizumab?

Rontalizumab is a special kind of immune particle called an antibody, and in this case it is a "monoclonal" antibody, meaning it only targets one kind of thing (in this case interferon-alpha). Rontalizumab is made by Genentech. Monoclonal antibodies look a lot like the antibodies that the body produces in response to infections or vaccines. Rontalizumab is a "humanized" monoclonal antibody, meaning that it is designed to resemble natural human antibodies as closely as possible. This is done to reduce the chance that the body will experience the drug as a foreign substance and attempt to eliminate it. This way, it is seen as something that belongs to a person and accepted much like the body’s own antibodies. Rontalizumab is given either through an intravenous infusion, or through subcutaneous injection (a shot under the skin, similar to an insulin injection).

What did the researchers hope to learn?

This study had several goals. Mainly, it was designed to test the safety of rontalizumab when given to patients with lupus and to reveal any side effects. In addition, the study was designed to find out whether the interferon signature that is found in most lupus patients can be suppressed after being giving rontalizumab, and how much drug it takes to achieve that effect. Blood samples donated by the patients who participated in the trial were obtained before and after receiving rontalizumab. The intensity of the interferon signature was measured using specialized assays developed specifically for this purpose.

Study Design

The study enrolled sixty patients with mildly active lupus. The study was conducted in the United States at 20 different study centers. In order to determine whether any side effects were due to study drug or due to other drugs, other medications were restricted during the study. For example, patients could receive no more than 20 mg of prednisone each day before entering into the trial, and could not be on strong immune-suppressing drugs such as Imuran or CellCept. Patients were divided into six groups. Eight out of 10 patients in each group received active drug, and two out of 10 patients in each group received only placebo (an inactive treatment). Neither patients nor physicians knew whether they received rontalizumab or placebo. The groups participated in the study one group at a time. Each group received a higher dose of study drug than the preceding one and patients were only enrolled in the next group after no serious side effects were seen in the one before. Doses of study drug ranged between 0.3- 10 mg per kg of body weight.

What were the study results?

Safety

The rate of side effects was similar between those patients who received placebo and those who received rontalizumab. Since interferon-alpha plays an important role in immune defense, particular attention was paid to any serious viral or bacterial infections. Although some patients developed common viral infections such as the common cold or stomach flu, the incidence of infections was not different between the placebo and the rontalizumab groups. Six patients had serious adverse events (events that led to hospitalizations), none of which were attributed to study drug by the treating physician. With the exception of one case of appendicitis, no serious infections have occurred in the trial to date. One patient developed cancer (leukemia) during the trial. Because of the small size of the trial, it is impossible to be sure whether or not this was related to the study drug.

Effect of rontalizumab on the interferon signature:

About half of the patients who participated in the trial had the interferon signature when they entered the trial. The other 50% of patients had levels similar to those found in healthy people. Increasing doses of rontalizumab led to a greater and greater drop in the levels of the signature that also lasted longer with higher doses of the drug. The lowest dose tested (0.3 mg/kg) was similar to placebo, and the highest dose tested (10 mg/kg) showed the most suppression of the interferon signature. The interferon signature tended to come back as drug levels in the blood decreased over time and, eventually, the signature returned to pre-study levels. Thus, it looked as if the drug achieved what it was supposed to do (i.e., reduce the activity of interferon-alpha by neutralizing the excessive amounts of interferon produced in patients with lupus).

What were the limitations of the study?

This was a small trial, as is typical for Phase I trials. Rare side effects can only be ruled out in much larger trials. It is not known whether the cancer that was seen is an isolated case or not and it would be impossible to know this for sure in a small study. If only one case is seen in a small trial, it makes sense to be careful until you have more information. If only one case is seen among thousands of patients, perhaps people would be less likely to worry that the treatment caused it.

The study was conducted in patients with mildly active lupus. Therefore, even though the trial demonstrated that rontalizumab has the intended effect on the interferon signature in patients with lupus, the drug’s effect on clinical symptoms of lupus (e.g., arthritis, skin rashes, and kidney disease) could not be reliably seen in this study. This will be the main goal of the next study, a larger, Phase II trial which is currently enrolling lupus patient volunteers.

What do the results mean for you?

Interferon-alpha is one of the most promising targets, at least in theory, for new treatments of lupus. Rontalizumab has passed the first stage in clinical testing. The Phase I trial showed that the drug seems safe enough to continue clinical development and that it is capable of reducing the activity of interferons in the body that may be promoting inflammation and autoimmune disease in patients with lupus. The results for this trial also helped narrow down the correct doses to carry forward to larger clinical trials.

Rontalizumab is now in the second phase of testing. The Phase II trial, called ROSE (Rontalizumab in Systemic Lupus Erythematosus), is currently enrolling patients with moderately to severely active lupus. The ROSE trial is conducted in about 100 centers in the United States, South America, and Europe.

For further information about this trial, you can go to http://clinicaltrials.gov/ct2/show/NCT00962832, or contact the Genentech clinical trials hotline at 888-662-6728.


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