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Roche Discussing Phase III Study with FDA for Personalized Asthma Drug Lebrikizumab


By Turna Ray

Roche subsidiary Genentech is planning a Phase III study to confirm early-stage findings suggesting that its investigational drug lebrikizumab will be efficacious for a molecularly defined subpopulation of asthma patients whose symptoms aren't managed properly with standard treatments.

"Lebrikizumab is a potential new therapeutic for asthma that is inadequately controlled despite inhaled corticosteroids and long-acting beta 2 agonists," a company spokesperson told PGx Reporter this week.

The company could not provide a specific timeline for the submission of a new drug application for lebrikizumab with the US Food and Drug Administration. However, the design of the Phase III study will allow Genentech to confirm that a subpopulation of patients who have elevated levels of a protein biomarker are responding especially well to lebrikizumab.

"We are targeting all asthmatics with uncontrolled disease despite high dose inhaled corticosteroids and a second controller who also have high serum periostin status," the Genentech spokesperson said in an e-mail.

To gauge these super-responders to lebrikizumab, Genentech will use a companion diagnostic developed by Roche to identify patients with elevated periostin, a protein secreted by interleukin-13 cytokines that is increased in patients with moderate to severe disease. "We are measuring both periostin high and periostin low subjects in Phase III (all comers) but we are seeking an indication in periostin-high subjects," the spokesperson said.

A Phase II study published earlier this month in the New England Journal of Medicine suggests that serum periostin levels can be used as a biomarker to gauge best responders to lebrikizumab, a monoclonal antibody that binds to and inhibits interleukin-13.

In this Phase II study, researchers discovered that patients with poorly controlled asthma respond well to lebrikizumab, but patients with high levels of periostin gain even more benefit when given lebrikizumab compared to placebo. Moreover, in the periostin-defined subpopulation, patients with high periostin do better on lebrikizumab than do patients with low periostin. "These findings suggest that the prespecified marker, serum periostin, could potentially be used to identify patients with asthma who may have an increased response to lebrikizumab treatment," write Jonathan Corren of the Allergy Medical Clinic in Los Angeles and colleagues in the NEJM paper.

Although these findings need to be confirmed in larger cohorts, the Phase II data "suggest the potential importance of biomarkers in identifying patients who will have a response to specific therapies for asthma," Corren et al. wrote.

Since the Phase II study results showed that the molecularly undifferentiated asthma patient population with poorly controlled disease also benefitted from lebrikizumab, it's possible that Genentech may be able to garner approval for the drug in the broader population, if Phase III results confirm efficacy and show that there are minimal drug-related adverse events. However, by pursuing a biomarker-based strategy the company is ensuring that it has the best chance of getting the drug approved, even if it is in a subset of the broader population.

Other drug developers have experienced regulatory and marketing setbacks when they chose to initially pursue a broader indication for treatments despite preliminary leads that a molecularly defined subset of patients may respond better to the drugs compared to the overall patient population. For example, Vectibix and Erbitux were already being marketed for the general metastatic colorectal cancer population, when data emerged that patients with KRAS mutations don't responde to these drugs.

Although there were preliminary leads in Vectibix's development program that EGFR inhibiting monoclonal antibodies may not work in patients harboring KRAS mutations, Amgen choose to gain approval in the broader population first. As such, when FDA decided to update the labeling for this class of drugs to recommend against prescribing them in the KRAS-mutated subpopulation, sponsors Amgen and Bristol-Myers Squibb had to submit pharmacogenomic analysis to the agency and ink deals to develop companion diagnostics to pick out best responders. These post-marketing uncertainties negatively impacted the sales of the two drugs (PGx Reporter 02/04/2009).

It appears that Genentech is trying to avoid such post-marketing difficulties by exploring a biomarker strategy for lebrikizumab early on.

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Lebrikizumab came under Genentech's portfolio with the 2007 acquisition of Tanox Pharmaceuticals. After completing dose-escalation studies with lebrikizumab in December of that year, Genentech launched the Phase II trial in October 2008.

The Phase II double-blind, parallel-group study sponsored by Genentech randomized more than 200 patients to either lebrikizumab or placebo once a month for six months. In order to partake in the study, patients had to undergo various tests to confirm they had uncontrolled asthma despite being treated with the standard treatments, such as inhaled glucocorticoids and long-acting beta agonists.

In addition to gauging patients' response to the investigational drug in the overall study population, the researchers analyzed the effect of lebrikizumab compared to placebo in patient subgroups stratified by an interleukin-13 signature surrogate (Th2 status) and periostin serum levels.

Interleukin-13 is a cell-signaling protein molecule secreted by T helper type 2 cells that has been shown to play a role in asthma. Although inhaled glucocorticoids inhibit interleukin-13, many asthma patients with elevated interleukin-13 don't respond properly to medium- to high-dose glucocorticoids. This suggests that heightened interleukin-13 may be associated with resistance to glucocorticoids.

The researchers noted that they sought a surrogate marker for interleukin-13 activity "because highly sensitive assays are required to quantify interleukin-13 in blood or airway samples." Since interleukin-13 causes epithelial cells to secrete the protein periostin, the researchers identified periostin levels as a surrogate for interleukin-13 activity, but when the Phase II study began three years ago, a periostin assay was not available for patient stratification. As such, the researchers initially used Th2 status, which involved assessing patients' serum IgE level and peripheral-blood eosinophil count. As the study progressed and before "treatment codes were broken," Corren et al. initiated "a statistical plan in which the groups were differentiated on the basis of serum periostin levels."

The primary study outcome was change in forced expiratory volume in 1 second, or FEV1, from baseline to 12 weeks into the study. In the overall study population, patients in the placebo arm experienced a 4.3 percent change in FEV1, while those in the lebrikizumab arm experienced a 9.8 percent change in FEV1. Subgroup analysis showed that patients treated with lebrikizumab who had low periostin levels had a change in FEV1 of 5.1 percent while those on placebo experienced a 3.5 percent change in FEV1. In patients with high periostin levels, lebrikizumab-treated patients saw an FEV1, change of 14 percent compared to those on placebo who had a 5.8 percent change.

Study investigators saw changes in FEV1 in participants after one week of starting lebrikizumab treatment and this effect was sustained throughout the study. "Subgroup analysis showed that the effectiveness of lebrikizumab treatment was greater in patients with high periostin levels than in patients with low periostin levels, as evidenced by both a more robust increased in FEV1 and greater decline in [measures of fractional exhaled nitric oxide]," the researchers wrote in the NEJM paper.

In post-hoc analysis, the researchers found that elevated Th2 status was not predictive of greater improvements in FEV1 with lebrikizumab treatment. Although analysis of subpopulations by both Th2 status and periostin levels were prespecified in the study protocols, "serum periostin was better at predicting benefit … than Th2 status for the primary endpoint and key secondary endpoint of severe exacerbations," the Genentech spokesperson said.

In the high Th2 subgroup, secondary outcome measures of asthma-related exacerbations were 60 percent lower in the lebrikizumab-treated group than those on placebo. The high periostin group treated with the investigational drug had a trend toward lower exacerbations than placebo-treated patients, with a 26 percent lower exacerbations rate that had a p-value of 0.40.

"Overall, there was a nonsignificant trend toward lower rates of severe exacerbations among patients in the lebrikizumab group than among patients in the placebo group (P=0.10)," the researchers wrote. "The observed rates of severe exacerbations were nonsignificantly reduced in subgroups according to periostin level and study treatment."

The safety analysis showed that patients in the lebrikizumab arm and those in the placebo group generally had similar frequencies of adverse events and serious adverse events. Musculoskeletal adverse events, such as back and joint pain, were more common in the lebrikizumab arm than in the placebo group, 13.2 percent versus 5.4 percent. Approximately 12 percent of the study population, 13 from the lebrikizumab arm and 12 from the placebo arm, dropped out of the study.

Currently doctors use a step-wise, trial-and-error method to determine the best treatment strategy for asthma patients who aren't responding well to inhaled corticosteroids. A molecularly guided strategy, such as the one being explored by Genentech with lebrikizumab, may provide more guidance for doctors treating poorly controlled asthmatics.

There are 17.5 million adults and 7.1 million children in the US with asthma, according to the Centers for Disease Control's 2009 statistics. Patients with poorly controlled asthma would represent some portion of this population, but Genentech did not provide an exact estimate for lebrikizumab's market size.

Given the medical complications associated with uncontrolled asthma there may be a strong cost-benefit advantage with the availability of a molecularly-guided asthma treatment.

A study published in the August issue of The Archives of Allergy, Asthma & Immunology showed there are high costs associated with asthmatics with poorly controlled disease. The trial, involving 628 children ages six to 12 with severe or difficult-to-treat asthma, found that direct costs of care were approximately 50 percent higher for poorly controlled asthma patients at $4,983 per year, compared to $3,236 for patients with not well controlled asthma, and $3,588 for those with well controlled asthma. Researchers calculated these costs in 2002 dollars, but in 2011 these costs would be 25 percent higher.

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