BTK Inhibitor Likely to Get a Pass to Phase III in Uncontrolled Asthma

SAN DIEGO — Treatment with an investigational oral Bruton’s tyrosine kinase (BTK) inhibitor was associated with numerical decreases in loss of asthma control (LOAC) events for patients with poorly controlled asthma in a randomized phase II study, though the reductions failed to meet criteria for significance.

In adults with moderate-to-severe asthma, fewer patients assigned to twice-daily rilzabrutinib at two different dose levels experienced LOAC events over 12 weeks of treatment compared with a placebo group, though neither difference was significant:

• 37.5% with 800-mg rilzabrutinib vs 50% with placebo (OR 0.57, 95% CI 0.20-1.61)
• 18.8% with 1,200 mg rilzabrutinib vs 29.4% with placebo (OR 0.58, 95% CI 0.25-1.35)

Rilzabrutinib was also associated with improved disease control on the 5-item Asthma Control Questionnaire (ACQ-5), according to Jessica Gereige, MD, of drugmaker Sanofi in Cambridge, Massachusetts, who presented the findings during a poster session at the American Thoracic Society (ATS) annual meeting.

The multicenter study randomized 196 patients with poorly controlled asthma despite moderate to high doses of inhaled corticosteroid and long-acting β2 adrenergic agonist (ICS/LABA) treatment. Patients were kept on their background therapy during the first 4 weeks of the trial, which was followed by an 8-week withdrawal period.

Gereige noted that scores on the ACS-5 decreased rapidly with the BTK inhibitor, reaching the threshold considered a minimum clinically important difference (MCID) — a decline of 0.5 on the 0 to 6 scale — whereas patients assigned to placebo never reached that MCID.

At 12 weeks, the least-squares mean change on the ACQ-5 was -0.70 and -0.85 points for the 800-mg and 1,200-mg rilzabrutinib groups, as compared with -0.12 and -0.31 points with placebo (nominal P values of 0.0184 and 0.0013, respectively, for the two comparisons).

“Those on rilzabrutinib, even after withdrawal of their background ICS/LABA, they never really go back to their baseline, they maintain that minimal clinically important difference,” Gereige said.

According to background information in the poster, BTK plays a key role in signaling in immune cells and airway inflammation. Drugs in this class are used to treat a range of hematologic malignancies involving B cells and are also being investigated in other conditions as well.

“B cells are important in the pathogenesis of asthma, and BTK inhibitors impact multiple important pathways including B-cell development, migration, and activation,” explained Linda Rogers, MD, of the Icahn School of Medicine at Mount Sinai and Mount Sinai National Jewish Health Respiratory Institute in New York City.

“BTK is also expressed in other cells, including mast cells, NK [natural killer] cells, T cells, macrophages, neutrophils, monocytes, and basophils, which play a role in asthma,” she added.

Rogers, who was not involved in the research, said that while an oral treatment would be an appealing option compared with the available injection therapies for severe asthma, BTK inhibitors will need to demonstrate their benefit in phase III trials with more patients and for longer treatment periods.

“This is really just a first step in considering BTK inhibitors as possible asthma treatments,” she said.

Rilzabrutinib is a reversible covalent BTK inhibitor under development by Sanofi that has previously demonstrated activity in pemphigus and immune thrombocytopenia and other conditions. The drugmaker said the results of the phase II data presented at ATS “support the further development and advancement into a phase III program” in moderate-to-severe asthma.

Gereige said a goal of the research is to ultimately test BTK inhibition earlier in the treatment paradigm to see if the agents can be disease modifying. “The hope is to start early and prevent those comorbidities that can happen after patients have asthma for a long period of time,” she told MedPage Today.

The double-blind phase II trial she presented included 62 patients in the low-dose cohort (32 assigned to 800 mg rilzabrutinib; 32 assigned to placebo) and 132 patients in the high-dose cohort (64 assigned to 1,200 mg rilzabrutinib; 68 assigned to placebo).

Patients had an average age of about 50 years, a majority were women, and over 90% were white. Patients had their asthma for more than 20 years on average. A predominance of patients in the lower-dose cohort were recruited from Latin America, while a predominance of patients in the high-dose cohort were recruited from Eastern Europe.

There was a higher proportion of patients with exacerbations in the prior year in the low-dose cohort (94% vs 68% in the high-dose cohort) and a greater proportion receiving high doses of ICS/LABA (88% vs 52%). In the high-dose cohort, there was less of a type 2 population and less history of atopy.

Rilzabrutinib was generally safe and well tolerated, according to Gereige.

For the low-dose cohort, treatment-emergent adverse events (AEs) occurred in 44% of the rilzabrutinib group and 63% of the placebo group, with serious AEs in two patients assigned to the BTK inhibitor (6.3%). In the high-dose cohort, treatment-emergent AEs occurred in 41% and 27%, respectively, with no serious AEs. Events leading to discontinuation were higher in the rilzabrutinib groups (11-13% vs 4-6% with placebo).

There were no imbalances in liver function tests and no AEs of interest with BTK inhibitors — cytopenia, hemorrhagic events, atrial fibrillation — were observed during the trial. No treatment-emergent AEs resulted in deaths in either of the cohorts.

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