Rezpegaldesleukin gets FDA fast track designation for atopic dermatitis
Key takeaways:
- Rezpegaldesleukin targets the IL-2 receptor complex to stimulate regulatory T-cell proliferation.
- Positive outcomes persisted for 36 weeks after treatment stopped at 12 weeks.
The FDA has granted a fast track designation to rezpegaldesleukin for treating patients aged 12 years and older with moderate to severe atopic dermatitis that topical therapies have not adequately controlled, according to a press release.
As an investigational biologic therapy, Nektar Therapeutics said in the release, rezpegaldesleukin targets the IL-2 receptor complex to stimulate the proliferation of regulatory T cells. A phase 1b study demonstrated the drug’s efficacy and safety, the company continued.
“Rezpegaldesleukin is a completely novel potential medicine,” Jonathan Zalevsky, PhD, chief research and development officer, Nektar Therapeutics, told Healio. “It’s a brand-new way to specifically target that regulatory population of T cells to try to harness them therapeutically.”
Other biologics such as dupilumab (Dupixent; Regeneron, Sanofi), lebrikizumab (Ebglyss, Lilly) and tralokinumab (Adbry, LEO Pharma) specifically target IL-13 receptors downstream of T-helper 2 responses that are dominant in many types of atopic dermatitis, Zalevsky explained.
“Rezpegaldesleukin is a completely different molecule,” he said. “It’s an agonist, not an antagonist. And as an agonist, it stimulates regulatory T cells, and these regulatory T cells block the underlying issue in patients with atopic dermatitis. They block the inflammation that’s happening in the dermis.”
Administered subcutaneously every 2 weeks through 12 weeks, doses in the phase 1b study included 12 µg/kg (n = 16; mean age, 47.9 years; 68.8% women) or 24 µg/kg (n = 17; mean age, 37.5 years; 41.2% women) of rezpegaldesleukin or placebo (n = 10; mean age, 42.5 years; 60% women).
Least square mean percentage improvements from baseline through 12 weeks in Eczema Area and Severity Index (EASI) scores included 83% for the 24 µg/kg group, 65% for the 12 µg/kg group, and 47% for the placebo group.
“We’ve really only seen results like that from a JAK inhibitor,” Zalevsky said. “It’s very rare that a biologic gives you that kind of magnitude of efficacy.”
Percentages of patients who achieved a 75% decrease in EASI scores or more at week 12 included 41% of the 24 µg/kg group, 25% for the 12 µg/kg group, and 20% for the placebo group.
Least square mean percentage improvements from baseline through 12 weeks in Body Surface Area scores included 72% for the 24 µg/kg group, 55% for the 12 µg/kg group, and 36% for the placebo group.
Percentages of patients who achieved a reduction in Daily Quality of Life Index (DLQI) scores of 4 points or more from baseline through week 12 included 75% of the 24 µg/kg group, 46% of the 12 µg/kg group and 30% of the placebo group.
Similar improvements were seen in validated Investigator Global Assessment and Itch Numeric Rating Scale scores as well.
Also, 76.5% of the 24 µg/kg group, 62.5% of the 12 µg/kg group and 80% of the placebo group experienced treatment-emergent adverse events, which all were mild to moderate in the treatment arms and were mostly reactions at the injection site.
Clinical activity was dose-dependent as well, Zalevsky said, with very rapid onset of efficacy that was much faster than the IL-13 biologics. Most importantly, he continued, although treatment stopped at 12 weeks, these results persisted for the next 36 weeks.
For example, mean percent reductions from baseline EASI at 48 weeks included 83.37% for the 24 µg/kg group, 71.81% for the 12 µg/kg group and 32.67% for the placebo group.
Mean percent reductions from baseline Body Surface Area at 48 weeks included 81.73% for the 24 µg/kg group, 62.83% for the 12 µg/kg group and 25% for the placebo group.
Proportions of patients who were DLQI responders at week 48 included 55.6% of the 24 µg/kg group, 25% of the 12 µg/kg group and 33.3% of the placebo group.
“There’s no rebound or relapse of the disease. If you were taking either a JAK inhibitor or an IL-13 inhibitor, you would relapse quite quickly after you stopped taking the drugs,” Zalevsky said. “You need those drugs. They symptomatically control the disease.”
Now, he said, the dermatology community is wondering if rezpegaldesleukin has any potential to induce remission in patients with atopic dermatitis.
Nektar Therapeutics has completed enrollment of 396 patients for its phase 2b trial of rezpegaldesleukin, which will investigate mean improvements in EASI scores at 16 weeks as well as validated Investigator Global Assessment and Itch Numeric Rating Scale scores.
Zalevsky said the company would like to replicate its phase 1b results in this phase 2b trial in addition to seeing what would happen with longer treatment.
“We already know that we have a level of remission, but we never actually tested what would have happened if we treated longer,” he said. “Would we see even more efficacy? Larger proportions of patients developing further and further definite response?”
After a 16-week induction period, participants in the phase 2b trial with a 50% decrease or better in EASI scores will be able to stay in the study through 52 weeks of maintenance. Treatment once every month or once every 3 months will follow.
“We think this could be a drug that is very convenient for patients, with something like a once every 3-month period or maybe even lower frequency with this administration and maintenance regimen,” Zalevsky said.
Nektar Therapeutics expects to have topline data from the phase 2b trial’s induction period later this year in June, followed by a registrational pathway including a meeting with the FDA to present the findings of the completed trial.
“Now that we have the fast track designation, we actually get additional attention, and we get more chances to interact and also faster turnaround time from the FDA as well,” Zalevsky said. “We would basically leverage all of that to present our plan.”
Zalevsky is optimistic about rezpegaldesleukin and its future in treatment for atopic dermatitis.
“It’s really fundamentally different,” he said, adding that rezpegaldesleukin treats the underlying conditions of atopic dermatitis.
“That’s why we think we see people that can go off drug and remain clean and without relapse for a long time,” he said. “That’s something that we’re really excited about, because that’s something that hasn’t been seen before in this disease.”
Reference:
- Silverberg J, et al. Efficacy and safety of single agent rezpegaldesleukin, a selective regulatory T-cell-inducing interleukin-2 conjugate, in the treatment of atopic dermatitis: Final results from a randomized phase 1b study. Presented at: 2023 EADV Congress, Oct. 11-14, 2023; Berlin.