Lung function improves for patients with asthma within 24 hours with rademikibart

Key takeaways:

• Rademikibart is an IL-4R alpha inhibitor that blocks IL-4 and IL-13 signaling.
• 77% of FEV₁ improvements happened within 24 hours.
• Patients with high eosinophil counts experienced greater improvements.

SAN FRANCISCO — Patients with moderate to severe asthma saw increases in FEV₁ within 24 hours after taking a loading dose of rademikibart, according to an abstract presented at the American Thoracic Society International Conference.

This rapid response suggests that the drug may have use in acute settings, Barry Quart, PharmD, chief executive officer, Connect Biopharma, told Healio.

“All of the biologics approved for asthma or COPD, regardless of what their target is, are approved for and used for chronic maintenance treatment for prevention of future exacerbations,” Quart said. “In fact, the package inserts for all of the biologics approved for asthma and COPD explicitly say, ‘should not be used to treat acute symptoms or acute exacerbations of asthma or COPD.’”

Barry Quart

Yet data for rademikibart indicate dramatic improvements in airway function the morning after the first dose, he continued, adding that the more than a million patients with asthma who visit the ED for an acute exacerbation each year have been treated the same way for more than 20 years.

“Those patients get steroids, and they get bronchodilators, and some of them get sent home. Some of them end up in the hospital for several days because they can’t get stabilized,” Quart said. “Nobody’s developing a biologic for this acute treatment setting.”

As a monoclonal antibody and next-generation IL-4R alpha inhibitor, rademikibart (CBP-201, Connect Biopharma) blocks IL-4 and IL-13 signaling.

Quart said that he and his colleagues have always considered rademikibart to be a second-generation dupilumab (Dupixent; Sanofi, Regeneron), which is another monoclonal antibody that targets IL-4 and IL-13 signaling. “However, they bind very differently based on a much more stable molecular structure with the IL-4 receptor complex,” he said. “Rademikibart, vs. what’s generally believed with biologics, works very rapidly after administration.”

The phase 2b trial included 322 patients with moderate to severe asthma who received 150 mg or 300 mg subcutaneous doses of rademikibart or placebo every 2 weeks for 24 weeks, followed by 8 weeks of follow-up.

The 150 mg group included 106 patients (mean age, 51.6 years; 66% women; 77.4% white), the 300 mg group included 108 patients (mean age, 52.7 years; 63% women; 81.5% white) and the placebo group included 108 patients (mean age, 54.8 years; 55.6% women; 73.1% white).

All patients began with a 600 mg loading dose of rademikibart or placebo and then conducted prebronchodilator FEV₁ measurements at home each day during the study.

“At 1 week, we had highly statistically significant, very clinically relevant improvements in airway function across all patients receiving rademikibart,” Quart said.

Improvements in FEV₁ for 129 patients in the cohort with T2-mediated asthma, defined by baseline eosinophil counts of 300 cells/L or higher, included 93 mL after 24 hours, 102 mL after 48 hours, and 121 mL after 168 hours, or 1 week. Specifically, 77% of these improvements occurred within 24 hours, and 84% of these improvements occurred within 48 hours.

This is the population of asthma patients currently being enrolled in the researchers ongoing phase 2 studies, Quart said.

“It was surprising to us that the product worked as quickly as it does,” Quart said.

The home spirometry readings were consistently lower and more variable than those conducted in clinic, said the researchers, attributing them to a possible lack of in-clinic coaching on proper technique by medical personnel.

In clinic, the researchers continued, FEV1 measurements improved by approximately 200 mL by the end of the first week and persisted through week 24 for the treatment groups, including improvements of 230 mL for the 150 mg group and 279 for the 300 mg group. The placebo group improved by 89 mL by week 24.

“The home spirometry data are definitely more variable than what we get in the clinic. Obviously, if I didn’t have that rock solid 1-week data in the clinic, it would be more tenuous to accept the home spirometry data,” Quart said.

“But we already know that we’re seeing several hundred milliliter improvements in airway function at 7 days, and it was unlikely that it all started on day 6 or day 5,” he continued. “The magnitude was so great on day 1, it was pretty hard not to believe that it is real data.”

Improvements were greater for patients with further markers of inflammatory-based asthma with baseline eosinophil counts of 300 cells/µL and higher and baseline FeNO levels of 25 ppb and higher (n = 90), including a 132 mL improvement at 24 hours, 160 mL improvement at 48 hours and 184 mL improvement at 168 hours.

Like the overall population, the researchers added, 72% of this improvement occurred within the first 24 hours, with 87% of this improvement occurring within the first 48 hours.

Among patients with T2-mediated asthma, exacerbation rates fell by 63% (P = .02) for the 150 mg group and by 73% (P = .04) for the 300 mg group as well.

The researchers also characterized the treatment-emergent adverse events as comparable between the groups, with most classified as grade 1 or 2. None of these events were due to eosinophilia.

“Dupixent has a surprising effect of increasing eosinophils, and the underlying cause of that has never really been described in the literature,” Quart said. “In fact, we see exactly the opposite. Rather than an increase in eosinophils, we see a general decrease.”

By group, 72.6% of the 150 mg group, 70.4% of the 300 mg group and 59.3% of the placebo group experienced at least one treatment-emergent adverse event.

Four patients in the 150 mg group, three in the 300 mg group and two in the placebo group discontinued treatment due to these events, all of which were resolved, and none of which were related to treatment.

There also were two serious treatment-emergent adverse events in the 150 mg group, three in the 300 mg group and three in the placebo group, the researchers continued, but none of them were related to rademikibart.

Based on these findings, the researchers concluded that patients experienced rapid improvements in lung function after receiving rademikibart, with most of these improvements occurring within the first 24 hours.

Further, the researchers said, these findings indicate that rademikibart has potential for early treatment among patients with asthma driven by type 2 inflammation after an acute exacerbation with sustained positive outcomes.

Next, the researchers will conduct a pair of trials examining the use of rademikibart in the acute treatment of patients experiencing an exacerbation.

“The goal there is to improve airway function very quickly so those patients can get out of the hospital and get home,” Quart said.

More than half of patients with exacerbations see their exacerbations get worse or have another exacerbation within the next 4 weeks, he continued.

“Hospitals don’t get paid if a patient comes back in that 4-week period,” Quart said. “It’s important to be able to show that we can prevent patients from returning to the ED, or the hospital, to help build the story as to why the hospital should pay the money to use this biologic.”

If approved, rademikibart would be the first biologic used in the hospital to treat patients with asthma, he said. Once these exacerbations are under control, he added, the researchers hope these patients would continue to use rademikibart for maintenance to prevent future exacerbations.

“Our market research also indicated that if the drug worked well in the acute setting, a large majority of clinicians said they’d love to keep the patient on it chronically,” Quart said. “That’s the Holy Grail.”
these data, Quart said, it will work with the FDA to build a phase 3 plan.

“Get the patient in when they’re having an acute exacerbation, treat them acutely, and then, after a month, initiate chronic treatment and follow them for the usual 52 weeks,” he said.

For more information:

Barry Quart, PharmD, can be reached at allergy@healio.com.